WORLD INTELLECTUAL PROPERTY ORGANIZATION
Internationa] Bureau
PCT
INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(51) International Patent Classification 6
C07D 401/00
A2
(11) International Publication Number: WO 98/52937
(43) International Publication Date: 26 November 1998 (26.1 1.98)
(21) International Application Number: PCT/US98/10807
(22) International Filing Date: 22 May 1998 (22.05.98)
(30) Priority Data:
60/047,535
22 May 1997 (22.05.97)
US
(71) Applicant (for all designated States except US): G.D. SEARLE
AND CO. [US/US]; P.O. Box 5110, Chicago, IL 60680
(US).
(72) Inventors; and
(75) Inventors/Applicants (for US only): ANANTANARAYAN,
Ashok [US/US]; 54 Lisk Drive, Hainesville, IL 60015
(US). CLARE, Michael [GB/US]; 5154 West Brown Street,
Skokie, IL 60077 (US). GENG, Lifeng [CN/US]; 5300
Davis Street, Skokie, IL 60077 (US). HANSON, Gunnar,
J. [US/US]; 7410 Keystone Avenue, Skokie, IL 60076
(US). PARTIS, Richard, A. [US/US]; 2221 Noyes Street,
Evanston, IL 60012 (US). STEALEY, Michael, A. [US/US];
502 Juniper Parkway, Libertyville, IL 60048 (US). WEIER,
Richard, M. [US/US]; 240 Hickory Court, Lake Bluff, IL
60044 (US).
(74) Agents: WILLIAMS, Scott, A. et al.; Senniger, Powers, Leavitt
& Roedel, 16th floor Fl, One Metropolitan Square, St.
Louis, MO 63102 (US).
(81) Designated States: AL, AM, AT, AU, AZ, BA, BB, BG, BR,
BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE,
GH, GM, GW, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ,
LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW,
MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL,
TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW, ARIPO
patent (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), Eurasian
patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European
patent (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR,
IE, IT, LU, MC, NL, PT, SE), OAPI patent (BF, BJ, CF,
CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG).
Published
Without international search report and to be republished
upon receipt of that report.
(54) Title: 3(5)-HETEROARYL SUBSTITUTED PYRAZOLES AS p38 KINASE INHIBITORS
(57) Abstract
A class of pyrazole derivatives is described for use in treating p38 kinase
mediated disorders. Compounds of particular interest are defined by Formula (I),
wherein R 1 , R 2 , Ar 1 and HetAr 2 are as described in the specification.
Ar
5
„ 2 N
N
(I)
R 1
FOR THE PURPOSES OF INFORMATION ONLY
Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
AL
Albania
ES
Spain
LS
Lesotho
SI
Slovenia
AM
Armenia
FI
Finland
LT
Lithuania
SK
Slovakia
AT
Austria
FR
France
LU
Luxembourg
SN
Senegal
AU
Australia
GA
Gabon
LV
Latvia
sz
Swaziland
AZ
Azerbaijan
GB
United Kingdom
MC
Monaco
TD
Chad
BA
Bosnia and Herzegovina
GE
Georgia
MD
Republic of Moldova
TG
Togo
BB
Barbados
GH
Ghana
MG
Madagascar
TJ
Tajikistan
BE
Belgium
GN
Guinea
MK
The former Yugoslav
TM
Turkmenistan
BF
Burkina Faso
GR
Greece
Republic of Macedonia
TR
Turkey
BG
Bulgaria
HU
Hungary
ML
Mali
TT
Trinidad and Tobago
BJ
Benin
IE
Ireland
MN
Mongolia
UA
Ukraine
BR
Brazil
IL
Israel
MR
Mauritania
UG
Uganda
BY
Belarus
IS
Iceland
MW
Malawi
US
United States of America
CA
Canada
IT
Italy
MX
Mexico
uz
Uzbekistan
CF
Central African Republic
JP
Japan
NE
Niger
VN
Viet Nam
CG
Congo
KE
Kenya
NL
Netherlands
YU
Yugoslavia
CH
Switzerland
KG
Kyrgyzstan
NO
Norway
zw
Zimbabwe
CI
Cote d'lvoire
KP
Democratic People's
NZ
New Zealand
CM
Cameroon
Republic of Korea
PL
Poland
CN
China
KR
Republic of Korea
PT
Portugal
CU
Cuba
KZ
Kazakstan
RO
Romania
CZ
Czech Republic
LC
Saint Lucia
RU
Russian Federation
DE
Germany
LI
Liechtenstein
SD
Sudan
DK
Denmark
LK
Sri Lanka
SE
Sweden
EE
Estonia
LR
Liberia
SG
Singapore
WO 98/52937 PCTYUS98/10807
1
3 (5) -HETEROARYL SUBSTITUTED PYRAZOLES
AS p3 8 KINASE INHIBITORS
5 Cross -Reference to Related Application
This application claims priority from U.S.
Provisional Application Serial No. 60/047,535 filed May
22, 1997.
Field of the Invention
This invention relates to a novel group of pyrazole
compounds, compositions and methods for treating p38
15 kinase mediated disorders.
Background of the Invention
Mitogen-act ivated protein kinases (MAP) is a family
20 of proline-directed serine/threonine kinases that
activate their substrates by dual phosphorylation. The
kinases are activated by a variety of signals including
nutritional and osmotic stress, UV light, growth factors,
endotoxin and inflammatory cytokines. The p3 8 MAP kinase
25 group is a MAP family of various isoforms, including
p38a, p38/3 and p38Y, and is responsible for
phosphorylating and activating transcription factors
(e.g. ATF2 , CHOP and MEF2C) as well as other kinases
(e.g. MAPKAP-2 and MAPKAP-3) . The p38 isoforms are
3 0 activated by bacterial lipopolysaccharide , physical and
chemical stress and by pro -inflammatory cytokines,
including tumor necrosis factor (TNF-a) and interleukin- 1
(IL-1) . The products of the p3 8 phosphorylation mediate
the production of inflammatory cytokines, including TNF
3 5 and IL-1, and cyclooxygenase-2 .
TNF-a is a cytokine produced primarily by activated
monocytes and macrophages. Excessive or unregulated TNF
WO 98/52937
PCT/US98/10807
production has been implicated in mediating a number of
diseases . Recent studies indicate that TNF has a
causative role in the pathogenesis of rheumatoid
arthritis. Additional studies demonstrate that
5 inhibition of TNF has broad application in the treatment
of inflammation, inflammatory bowel disease, multiple
sclerosis and asthma.
TNF has also been implicated in viral infections,
such as HIV, influenza virus, and herpes virus including
10 herpes simplex virus type-1 (HSV-1) , herpes simplex virus
type-2 (HSV-2), cytomegalovirus (CMV) , varicella-zoster
virus (VZV) , Epstein-Barr virus, human herpesvirus- 6
(HHV-6) , human herpesvirus - 7 (HHV-7) , human herpesvirus - 8
(HHV-8) , pseudorabies and rhinotracheit is , among others.
15 IL-8 is another pro -inflammatory cytokine, which is
produced by mononuclear cells, fibroblasts, endothelial
cells, and kerat inocytes , and is associated with
conditions including inflammation.
IL-1 is produced by activated monocytes and
20 macrophages and is involved in the inflammatory response.
IL-1 plays a role in many pathophysiological responses
including rheumatoid arthritis, fever and reduction of
bone resorption.
TNF, IL-1 and IL-8 affect a wide variety of cells
25 and tissues and are important inflammatory mediators of a
wide variety of disease states and conditions. The
inhibition of these cytokines by inhibition of the p38
kinase is of benefit in controlling, reducing and
alleviating many of these disease states.
30 Various pyrazoles have previously been described.
U.S. Patent No. 4,000,281, to Beiler and Binon, describes
4,5-aryl, heteroaryl substituted pyrazoles with antiviral
activity against both RNA and DNA viruses such as
myxoviruses, adenoviruses, rhinoviruses , and various
35 viruses of the herpes group. WO 92/19615, published
November 12, 1992, describes pyrazoles as novel
WO 98/52937
PCTVUS98/10807
fungicides. U. S. Patent No. 3,984,431, to Cueremy and
Renault, describes derivatives of pyrazole-5-acetic acid
as having antiinflammatory activity. Specifically, [1-
isobutyl-3 , 4-diphenyl-lH-pyrazol-5-yl] acetic acid is
5 described. U. S. Patent No. 3,245,093 to Hinsgen et al ,
describes a process for preparing pyrazoles. WO
83/00330, published February 3, 1983, describes new
process for the preparation of diphenyl-3 , 4-methyl-5-
pyrazole derivatives. WO 95/06036, published for
10 preparing pyrazole and its derivatives. U.S. patent
5,589,439, to T. Goto, et al . , describes tetrazole
derivatives and their use as herbicides. EP 515041
describes pyrimidyl substituted pyrazole derivatives as
novel agricultural fungicides. Japanese Patent 4,145,081
15 describes pyrazolecarboxylic acid derivatives as
herbicides used in paddy fields, dry fields as well as
non-agricultural areas. Japanese Patent 5,345,772
describes novel pyrazole derivatives having potent
inhibitory activity against acetylcholinesterase.
2 0 Pyrazoles have been described for use in the
treatment of inflammation. Japanese Patent 5,017,470
describes synthesis of pyrazole derivatives as anti-
inflammatory, ant i -rheumatic , ant i -bacterial and anti-
viral drugs. EP 115640, published December 30, 1983,
25 describes 4 -imidazolyl -pyrazole derivatives as inhibitors
of thromboxane synthesis. 3- (4-Isopropyl-l-
methylcyclohex-l-yl) -4- ( imidazol - 1 -yl ) -lH-pyrazole is
specifically described. WO 97/01551, published January
16, 1997, describes pyrazole compounds as adenosine
30 antagonists. 4 - ( 3 -Oxo-2 , 3 -dihydropyridazin- 6-yl ) -3 -
phenylpyrazole is specifically described. U.S. Patent
No. 5,134,142, to Matsuo et al . describes 1,5-diaryl
pyrazoles as having ant i - inflammatory activity.
U.S. Patent No. 5,55 9,13 7 to Adams et al , describes
3 5 novel pyrazoles ( 1 , 3 , 4 , -substituted) as inhibitors of
cytokines used in the treatment of cytokine diseases.
WO 98/52937
PCT/US98/10807
4
Specifically, 3- (4 - f luorophenyl ) -1- (4-
methylsulf inylphenyl) -4- (4-pyridyl) -5H-pyrazole is
described. WO 96/03385, published February 8, 1996,
describes 3 , 4 - substituted pyrazoles, as having anti-
5 inflammatory activity. Specifically, 4 - [1 -ethyl -4 - (4 -
pyridyl ) - 5- trif luoromethyl -lH-pyrazol -3 -
yl ] benzenesulf onamide is described.
The invention's pyrazolyl compounds are found to
show usefulness as p38 kinase inhibitors.
Description of the Invention
A class of substituted pyrazolyl compounds useful in
treating p38 mediated disorders is defined by Formula I:
15
wherein
R 1 is selected from hydrido, alkyl, cycloalkyl,
alkenyl, alkynyl, heterocyclyl , cycloalkylalkylene ,
2 0 haloalkyl, hydroxyalkyl , aralkyl , alkoxyalkyl,
mercaptoalkyl , alkyl thioalkylene , amino, alkylamino,
arylamino, aminoalkyl, alkylaminoalkylene ,
heterocyclylalkylene , aminocarbonylalkylene , and
alkylaminocarbonylalkylene ; and
2 5 R 2 is selected from hydrido, alkyl, alkenyl, alkynyl,
heterocyclyl, haloalkyl, heterocyclylalkyl , amino,
alkylamino, aminoalkyl, alkoxy, alkylthio, carboxy,
alkoxycarbonyl , carboxyalkyl , aminocarbonylamino ,
10
N
(I)
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PCT/US98/10807
alkylaminocarbonylamino , alkylsulf onyl , aminosulf onyl ,
alkylsulf onylamino, aminosulf onyl amino ,
alkylaminosulf onylamino , and alkynylamino ; wherein the
heterocyclyl and heterocyclylalkyl groups are optionally
5 substituted with one or more radicals independently
selected from alkylthio, alkylsulf onyl , alkylsulf inyl ,
halo, alkyl, alkoxy, aryloxy, aralkoxy, heterocyclyl,
haloalkyl , amino, cyano, and hydroxy; and
Ar 1 is aryl optionally substituted with one or more
10 radicals independently selected from halo, alkyl,
alkenyl , alkynyl , alkoxy, alkenoxy, alkyldioxy,
alkylthio, alkylsulf inyl , alkylsulf onyl , amino,
aminocarbonyl , cyano, alkoxycarbonyl , formyl,
aminosulf onyl , alkylamino, nitro, arylamino,
15 alkylcarbonylamino, halosulf onyl , aminoalkyl, and
haloalkyl ; and
HetAr 2 is pyridinyl, pyrimidinyl or quinolinyl
optionally substituted with one or more radicals
independently selected from alkylthio, alkylsul f onyl ,
20 alkylsulf inyl , halo, alkyl, heterocyclyl, alkoxy,
aralkoxy, haloalkyl, amino, cyano, aralkyl, alkylamino,
cycloalkylamino, cycloalkenylamino, arylamino,
alkynylamino, and aralkylamino ,- or
a pharmaceutically-acceptable salt or a tautomer
25 thereof.
Compounds of Formula I would be useful for, but not
limited to, the treatment of any disorder or disease
state in a human, or other mammal, which is excacerbated
or caused by excessive or unregulated TNF or p3 8 kinase
3 0 production by such mammal . Accordingly, the present
invention provides a method of treating a cytokine-
mediated disease which comprises administering an
effective cytokine -interfering amount of a compound of
Formula I, or a pharmaceutically acceptable salt or
35 tautomer thereof.
WO 98/52937
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6
Compounds of Formula I would be useful for, but not
limited to, the treatment of inflammation in a subject,
and for use as antipyretics for the treatment of fever.
Compounds of the invention would be useful to treat
5 arthritis, including but not limited to, rheumatoid
arthritis, spondyloarthropathies, gouty arthritis,
osteoarthritis, systemic lupus erythematosus and juvenile
arthritis, osteoarthritis, gouty arthritis and other
arthritic conditions. Such compounds would be useful for
10 the treatment of pulmonary disorders or lung
inflammation, including adult respiratory distress
syndrome, pulmonary sarcoidosis, asthma, silicosis, and
chronic pulmonary inflammatory disease. The compounds
are also useful for the treatment of viral and bacterial
15 infections, including sepsis, septic shock, gram negative
sepsis, malaria, meningitis, cachexia secondary to
infection or malignancy, cachexia secondary to acquired
immune deficiency syndrome (AIDS) , AIDS, ARC (AIDS
related complex), pneumonia, and herpesvirus. The
2 0 compounds are also useful for the treatment of bone
resorption diseases, such as osteoporosis, endotoxic
shock, toxic shock syndrome, reperfusion injury,
autoimmune disease including graft vs. host reaction and
allograft rejections, cardiovascular diseases including
25 atherosclerosis, thrombosis, congestive heart failure,
and cardiac reperfusion injury, renal reperfusion injury,
liver disease and nephritis, and myalgias due to
infection .
The compounds are also useful for the treatment of
30 influenza, multiple sclerosis, cancer, diabetes, systemic
lupus erthrematosis (SLE) , skin-related conditions such
as psoriasis, eczema, burns, dermatitis, keloid
formation, and scar tissue formation. Compounds of the
invention also would be useful to treat gastrointestinal
35 conditions such as inflammatory bowel disease, Crohn's
disease, gastritis, irritable bowel syndrome and
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ulcerative colitis . The compounds would also be useful
in the treatment of ophthalmic diseases, such as
retinitis, retinopathies, uveitis, ocular photophobia,
and of acute injury to the eye tissue. Compounds of the
5 invention also would be useful for treatment of
angiogenesis , including neoplasia; metastasis;
ophthalmological conditions such as corneal graft
rejection, ocular neovascularization, retinal
neovascularization including neovascularization following
10 injury or infection, diabetic retinopathy, retrolental
fibroplasia and neovascular glaucoma; ulcerative diseases
such as gastric ulcer; pathological, but non-malignant,
conditions such as hemaginomas, including invantile
hemaginomas, angiofibroma of the nasopharynx and
15 avascular necrosis of bone; diabetic nephropathy and
cardiomyopathy; and disorders of the female reproductive
system such as endometriosis. The compounds of the
invention may also be useful for preventing the
production of cyclooxygenase-2 .
2 0 Besides being useful for human treatment, these
compounds are also useful for veterinary treatment of
companion animals, exotic animals and farm animals,
including mammals, rodents, and the like. More preferred
animals include horses, dogs, and cats.
2 5 The present compounds may also be used in co-
therapies, partially or completely, in place of other
conventional antiinflammatories, such as together with
steroids, cyclooxygenase-2 inhibitors, NSAIDs, DMARDS,
immunosuppressive agents, 5 -lipoxygenase inhibitors, LTB 4
30 antagonists and LTA 4 hydrolase inhibitors.
As used herein, the term "TNF mediated disorder"
refers to any and all disorders and disease states in
which TNF plays a role, either by control of TNF itself,
or by TNF causing another monokine to be released, such
35 as but not limited to IL-1, IL-6 or IL-8. A disease state
in which, for instance, IL-1 is a major component, and
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whose production or action, is exacerbated or secreted in
response to TNF, would therefore be considered a disorder
mediated by TNF .
As used herein, the term "p38 mediated disorder"
5 refers to any and all disorders and disease states in
which p3 8 plays a role, either by control of p3 8 itself,
or by p3 8 causing another factor to be released, such as
but not limited to IL-1, IL-6 or IL-8. A disease state
in which, for instance, IL-1 is a major component, and
10 whose production or action, is exacerbated or secreted in
response to p38, would therefore be considered a disorder
mediated by p38.
As TNF-/3 has close structural homology with TNF-a
(also known as cachectin) , and since each induces similar
15 biologic responses and binds to the same cellular
receptor, the synthesis of both TNF-o; and TNF-/S are
inhibited by the compounds of the present invention and
thus are herein referred to collectively as "TNF" unless
specifically delineated otherwise.
2 0 A preferred class of compounds consists of those
compounds of Formula I wherein
R 1 is selected from hydrido, lower alkyl , lower
cycloalkyl, lower cycloalkylalkylene , lower haloalkyl,
lower hydroxyalkyl , lower alkenyl , lower alkynyl , lower
2 5 heterocyclyl , lower aralkyl, lower alkoxyalkyl, lower
mercaptoalkyl , lower alkylthioalkylene , amino, lower
alkylamino, lower arylamino, lower aminoalkyl , lower
alkylaminoalkylene , lower heterocyclylalkylene , lower
aminocarbonylalkylene , and lower
30 alkylaminocarbonylalkylene ; and
R 2 is selected from hydrido, lower alkyl, lower
alkenyl, lower alkynyl, lower haloalkyl, lower
heterocyclyl, lower heterocyclylalkylene, amino, lower
alkylamino, lower alkynylamino, lower aminoalkyl, lower
3 5 alkylthio, lower carboxy, lower alkoxycarbonyl , lower
carboxyalkyl , lower aminocarbonyl amino, lower
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alkylaminocarbonylamino, lower alkylsulf onyl , lower
aminosulf onyl , lower alkylsulf onyl amino , lower
aminosul f onyl amino , and lower alkylaminosulf onylamino,
wherein the heterocyclyl and heterocyclylalkyl groups are
5 optionally substituted with one or more radicals
independently selected from lower alkylthio, lower
alkylsulf onyl , lower alkylsulf inyl , halo, lower alkyl,
lower alkoxy, aryloxy, lower heterocyclyl, lower
haloalkyl, amino, and cyano; and
10 Ar 1 is selected from phenyl, biphenyl, and naphthyl ,
wherein Ar 1 is optionally substituted with one or more
radicals independently selected from lower alkylthio,
lower alkylsulf onyl , aminosulf onyl , halo, lower alkyl,
lower alkenyl, lower alkynyl , lower alkylsulf inyl , cyano,
15 lower alkoxycarbonyl , aminocarbonyl , f ormyl , lower
alkylcarbonylamino , lower haloalkyl, lower alkoxy, lower
alkenyloxy, lower alkyldioxy, amino, lower alkylamino,
lower aminoalkyl, arylamino, nitro, and halosulf onyl ; and
HetAr 2 is pyridinyl or pyrimidinyl optionally
2 0 substituted with one or more radicals independently
selected from lower alkylthio, lower alkylsulf onyl , lower
alkylsulf inyl , halo, lower alkyl, lower heterocyclyl,
lower alkoxy, lower aralkoxy, lower haloalkyl, amino,
cyano, lower aralkyl , lower alkylamino, lower
2 5 cycloalkylamino, lower arylamino, lower alkynylamino , and
lower aralkylamino ; or
a pharmaceutically-acceptable salt or tautomer
thereof .
A class of compounds of particularly interest
3 0 consists of these compounds of Formula I wherein
R 1 is selected from hydrido, methyl, ethyl,
isopropyl, tert -butyl, isobutyl, trichloroethyl ,
pentaf luoroethyl , heptaf luoropropyl , dif luoroethyl ,
dif luoropropyl , dichloroethyl , dichloropropyl , vinyl,
3 5 allyl, ethynyl, propargyl , morpholinyl, piper idinyl ,
piperazinyl, benzyl, phenylethyl, morpholinomethyl ,
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morpholinoethyl , pyrrol idinylmethyl , piperazinylmethyl ,
piperidinylmethyl , pyridinylmethyl , thienylmethyl ,
methoxymethyl , ethoxymethyl , amino, methyl ami no,
dimethyl amino , phenylamino, methyl aminome thyl ,
5 dimethylaminomethyl , methyl ami noe thyl ,
dimethylaminoethyl , cyclopropyl, cyclopentyl, cyclohexyl,
eye lohexylme thyl , hydroxymethyl , hydroxyethyl ,
methylthio, and me thyl t hi ome thyl ; and
R 2 is selected from hydrido, methyl, ethyl, propyl,
10 isopropyl, tert -butyl, isobutyl, f luoromethyl ,
dif luoromethyl , trif luoromethyl , chloromethyl ,
dichloromethyl , trichloromethyl , pentaf luoroethyl ,
heptaf luoropropyl , dif luorochloromethyl ,
dichlorof luoromethyl , dif luoroethyl , dif luoropropyl ,
15 dichloroethyl , dichloropropyl , amino, N-methylamino , N,N-
dimethylamino, ethynylamino , propargylamino , piper idinyl,
piperazinyl, morpholinomethyl , pyrrol idinylmethyl ,
piperazinylmethyl, piperidinylmethyl, pyridinylmethyl,
thienylmethyl, thiazolylmethyl , oxazolylmethyl ,
2 0 pyrimidinylmethyl , quinolylmethyl , isoquinolinylmethyl ,
imidazolylmethyl , benzimidazolylmethyl , f urylmethyl ,
pyrazinylmethyl , aminocarbonylamino ,
methylaminocarbonylamino , dimethylaminocarbonylamino,
ethylaminocarbonylamino , diethylaminocarbonylamino ,
25 methylsulf onylamino , ethyl sulfonyl amino,
aminosul f onylamino , methyl aminosul f onylamino ,
dimethylaminosulf onylamino , ethyl aminosul f onylamino, and
diethylaminosulf onylamino ; and
Ar 1 is selected from phenyl, biphenyl , and naphthyl ,
3 0 wherein Ar 1 is optionally substituted with one or more
radicals independently selected from methylthio,
methylsulf inyl , methylsulf onyl , fluoro, chloro, bromo,
aminosul f onyl , methyl, ethyl, isopropyl, tert -butyl,
isobutyl, cyano, methoxycarbonyl , ethoxycarbonyl ,
35 aminocarbonyl , methyl carbonyl amino , trif luoromethyl ,
dif luoromethyl , f luoromethyl , trichloromethyl.
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dichloromethyl , chloromethyl , allyl, vinyl, ethynyl ,
propargyl , methoxy, ethoxy, propyloxy, n-butoxy, amino,
methylamino , ethylamino, dimethyl amino, diethylamino,
aminomethyl , aminoethyl, N-methyl, N- phenyl amino ,
5 phenylamino, diphenyl amino , nitro, and chlorosulf onyl ,-
and
HetAr 2 is selected from pyridinyl and pyrimidinyl,
wherein HetAr 2 is optionally substituted with one or more
radicals independently selected from methylthio,
10 methylsulf inyl , methylsulf onyl , fluoro, chloro, bromo,
methyl, ethyl, isopropyl, tert -butyl, isobutyl, methoxyl,
ethoxyl, phenoxyl , benzoxyl , phenethyl, trif luoromethyl ,
f luoromethyl , dif luoromethyl , amino, benzylamino,
propargylamino , cyclopropylamino , cyclobutylamino ,
15 eye lopentyl amino, and cyano; or
a pharmaceutically-acceptable salt or tautomer
thereof .
A class of compounds of specific interest consists
of those compounds of Formula I wherein
20 R 1 is hydrido, methyl, ethyl, hydroxyethyl ,
propargyl, dimethylaminoethyl or morpholinoethyl ; and
R 2 is selected from hydrido, methyl, ethyl, amino,
aminocarbonylamino , methylaminocarbonylamino,
methylsulf onyl ami no , aminosulf onyl amino, and
2 5 methylaminosulf onylamino ; and
Ar 1 is phenyl optionally substituted with one or more
radicals independently selected from methylthio,
methylsulf inyl , methylsulf onyl , fluoro, chloro, bromo,
aminosulf onyl , methyl, ethyl, isopropyl, tert -butyl,
30 isobutyl, cyano, methoxycarbonyl , ethoxycarbonyl ,
aminocarbonyl , methylcarbonylamino , trif luoromethyl ,
dif luoromethyl , f luoromethyl , trichloromethyl ,
dichloromethyl, chloromethyl, methoxy, ethoxy, propyloxy,
n-butoxy, amino, methylamino, ethylamino, dimethylamino,
3 5 diethylamino , aminomethyl, aminoethyl, N-methyl, N-
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phenylamino , phenylamino, diphenyl amino, nitro, and
chlorosulf onyl ; and
HetAr 2 is optionally substituted with one or more
radicals independently selected from methylthio,
5 methyl sulf inyl , methyl sul f onyl , fluoro, chloro, bromo,
methyl, ethyl, isopropyl, tert -butyl, isobutyl, methoxyl ,
ethoxyl, phenoxyl , benzoxyl , trif luoromethyl ,
f luoromethyl , dif luoromethyl , amino, propargylamino , and
cyano ; or
10 a pharmaceutically-acceptable salt or a tautomer
thereof .
A class of compounds of very specific interest
consists of those compounds of Formula I wherein
R 1 is hydrido or methyl; and
15 R 2 is hydrido or methyl; and
Ar 1 is phenyl which is optionally substituted with
one or more radicals independently selected fluoro,
chloro, methyl, ethyl, trif luoromethyl , methoxy, ethoxy,
dimethyl amino, and nitro; and
20 HetAr 2 is optionally substituted with one or more
radicals independently selected from methyl, chloro,
fluoro, and trif luoromethyl ; or
a pharmaceutically-acceptable salt or tautomer
thereof .
25 A family of specific compounds of particular
interest within Formula I consists of compounds, and
tautomers and pharmaceutically-acceptable salts thereof,
as follows:
4 - (3 -methyl -4 -phenyl- lH-pyrazol - 5 -yl) pyridine ;
3 0 4- (4 -f luorophenyl ) -5- (4 -pyridinyl ) -lH-pyrazol-3-amine;
N- [4 (4 -f luorophenyl ) -5- (4 -pyridinyl ) - lH-pyrazol - 3 -
yl] methanesulf onamide ;
N- [4- (4 -f luorophenyl) -5- ( 4 -pyridinyl ) - lH-pyrazol - 3 -yl ] -
N' -methylsulf amide ;
3 5 [4 - (4 -f luorophenyl ) -5 - (4 -pyridinyl ) - lH-pyrazol -3 -yl] urea ;
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[4- (4 - f luorophenyl ) -5- (4 -pyridinyl ) -lH-pyrazol-3 -
yl] sulf amide;
4- (4 -chlorophenyl ) -l-methyl-3- (4 -pyridinyl ) - lH-pyrazol - 5 -
amine ;
5 N- [4- (4 - f luorophenyl) -5- (4 -pyridinyl ) - lH-pyrazol - 3 -yl ] -
N' -methylurea;
4- [4- (4 - f luorophenyl ) -lH-pyrazol -3 -yl] pyridine ;
4 - [4 - (4 - f luorophenyl ) -1 -methyl - lH-pyrazol -3 -yl] pyridine ;
4- (4 -f luorophenyl) -3- (4 -pyridinyl ) - lH-pyrazole- 1 -ethanol ;
10 4- (4 -f luorophenyl) -N, N-dimethyl - 3 - (4 -pyridinyl ) -1H-
pyrazole - 1 -ethanamine ;
4- [2- [4- (4 -f luorophenyl) -3- (4 -pyridinyl ) - lH-pyrazol - 1 -
yl ] ethyl ] morphol ine ;
4- [4- (4 -chlorophenyl) -lH-pyrazol -3 -yl] pyridine;
15 4- (4 -phenyl -lH-pyrazol- 5 -yl) pyridine;
1 -methyl -4- [2- [4- (4 -f luorophenyl) -3- (4 -pyridinyl ) -1H-
pyrazol - 1 -yl ] ] piperidine ; and
1 -methyl -4- [2- [4- (4 - f luorophenyl ) -5- (4 -pyridinyl ) -1H-
pyrazol - 1 -yl ] piperidine .
20 The term "hydrido" denotes a single hydrogen atom
(H) . This hydrido radical may be attached, for example,
to an oxygen atom to form a hydroxyl radical or two
hydrido radicals may be attached to a carbon atom to form
a methylene (-CH 2 -) radical. Where used, either alone or
25 within other terms such as "haloalkyl", "alkylsulf onyl " ,
" alkoxyalkyl " , " hydroxy alkyl " , "mercaptoalkyl " , the term
"alkyl" embraces linear or branched radicals having one
to about twenty carbon atoms or, preferably, one to about
twelve carbon atoms . More preferred alkyl radicals are
3 0 "lower alkyl" radicals having one to about ten carbon
atoms. Most preferred are lower alkyl radicals having
one to about six carbon atoms. Examples of such radicals
include methyl, ethyl, n-propyl, isopropyl, n-butyl ,
isobutyl, sec-butyl, tert-butyl, pentyl , iso-amyl, hexyl
35 and the like. The term "alkenyl" embraces linear or
branched radicals having at least one carbon- carbon
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double bond of two to about twenty carbon atoms or,
preferably, two to about twelve carbon atoms. More
preferred alkenyl radicals are "lower alkenyl" radicals
having two to about six carbon atoms . Examples of
5 alkenyl radicals include ethenyl , propenyl , allyl,
propenyl , butenyl and 4 -methylbutenyl . The terms
"alkenyl" and "lower alkenyl", embrace radicals having
"cis" and "trans" orientations, or alternatively, "E" and
"Z" orientations. The term "alkynyl" embraces linear or
10 branched radicals having at least one carbon-carbon
triple bond of two to about twenty carbon atoms or,
preferably, two to about twelve carbon atoms. More
preferred alkynyl radicals are "lower alkynyl" radicals
having two to about six carbon atoms. Examples of
15 alkynyl radicals include propargyl , 1-propynyl, 2-
propynyl , 1-butyne, 2 -butenyl and 1-pentynyl. The term
"cycloalkyl" embraces saturated carbocyclic radicals
having three to about twelve carbon atoms . More
preferred cycloalkyl radicals are "lower cycloalkyl"
20 radicals having three to about eight carbon atoms.
Examples of such radicals include cyclopropyl,
cyclobutyl, cyclopentyl and cyclohexyl. The term
" cycloalkylalkylene" embraces alkyl radicals substituted
with a cycloalkyl radical . More preferred
25 cycloalkylalkylene radicals are "lower
cycloalkylalkylene" which embrace lower alkyl radicals
substituted with a lower cycloalkyl radical as defined
above. Examples of such radicals include
cyclopropylmethyl , cyclobutylmethyl , cyclopentylmethyl
3 0 and cyclohexylmethyl . The term " cycloalkenyl " embraces
partially unsaturated carbocyclic radicals having three
to twelve carbon atoms and one or two double bonds but
not necessarily conjugated ( " cycloalkyldienyl " ) . More
preferred cycloalkenyl radicals are "lower cycloalkenyl"
3 5 radicals having four to about eight carbon atoms.
Examples of such radicals include cyclobutenyl ,
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cyclopentenyl and cyclohexenyl . The term
" cycloalkenylalkylene " embraces alkyl radicals
substituted with a cycloalkenyl radical . More preferred
cycloalkenylalkylene radicals are "lower
5 cycloalkenylalkylene" which embrace lower alkyl radicals
substituted with a lower cycloalkenyl radical, as defined
above. Examples of such radicals include
cyclobutenylmethyl , cyclopentenylmethyl and
cyclohexenylmethyl . The term "halo" means halogens such
10 as fluorine, chlorine, bromine or iodine. The term
"haloalkyl" embraces radicals wherein any one or more of
the alkyl carbon atoms is substituted with halo as
defined above. Specifically embraced are monohaloalkyl ,
dihaloalkyl and polyhaloalkyl radicals . A monohaloalkyl
15 radical, for one example, may have either an iodo, bromo,
chloro or f luoro atom within the radical . Dihalo and
polyhaloalkyl radicals may have two or more of the same
halo atoms or a combination of different halo radicals .
"Lower haloalkyl" embraces radicals having one to six
2 0 carbon atoms. Examples of haloalkyl radicals include
f luoromethyl , dif luoromethyl , trif luoromethyl ,
chloromethyl , dichloromethyl , trichloromethyl ,
pentaf luoroethyl , heptaf luoropropyl ,
dif luorochloromethyl , dichlorof luoromethyl ,
2 5 dif luoroethyl , dif luoropropyl , dichloroethyl and
dichloropropyl . The term " hydroxy alkyl " embraces linear
or branched alkyl radicals having one to about ten carbon
atoms, any one of which may be substituted with one or
more hydroxyl radicals. More preferred hydroxyalkyl
3 0 radicals are "lower hydroxyalkyl" radicals having one to
six carbon atoms and one or more hydroxyl radicals.
Examples of such radicals include hydroxymethyl ,
hydroxyethyl , hydroxypropyl , hydroxybutyl and
hydroxyhexyl . The terms "alkoxy" and "alkyloxy" embrace
35 linear or branched oxy- containing radicals each having
alkyl portions of one to about ten carbon atoms. More
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preferred alkoxy radicals are "lower alkoxy" radicals
having one to six carbon atoms. Examples of such
radicals include methoxy, ethoxy, propoxy, butoxy and
tert-butoxy. The term "alkoxyalkyl " embraces alkyl
5 radicals having one or more alkoxy radicals attached to
the alkyl radical to form, for example, mono alkoxyalkyl
and dialkoxyalkyl radicals. The "alkoxy" radicals may be
further substituted with one or more halo atoms, such as
fluoro, chloro or bromo, to provide "haloalkoxy"
10 radicals.
The term "aryl", alone or in combination, means a
carbocyclic aromatic system containing one, two or three
rings wherein such rings may be attached together in a
pendent manner or may be fused. More preferred aryl are
15 6-12 membered aryl radicals. Examples of such radicals
include phenyl, naphthyl , tetrahydronaphthyl , indane and
biphenyl . Aryl moieties may also be substituted at a
subst itutable position with one or more substituents
selected independently from, for example, halo, alkyl,
20 alkenyl , alkynyl, alkoxy, alkenoxy, alkyldioxy,
alkylthio, alkylsulf inyl , alkylsulf onyl , amino,
aminocarbonyl , cyano, alkoxycarbonyl , f ormyl ,
aminosulf onyl , alkylamino, nitro, arylamino,
al kylcarbonyl amino , halosulf onyl , aminoalkyl , and
25 haloalkyl, alkoxyalkyl, alkyl aminoalkyl , carboxyalkyl ,
alkoxycarbonylalkyl , aminocarbonylalkyl , aralkoxy,
hydroxyl , acyl , carboxy, aminocarbonyl, and
aralkoxycarbonyl . The term "alkyldioxy" encompasses an
alkyldioxy bridge, such as a methyl enedioxy bridge,
3 0 between two carbon ring atoms of an aryl moiety.
The term "heterocyclyl " embraces saturated,
partially unsaturated and unsaturated heteroatom-
containing ring-shaped radicals, which can also be called
"heterocyclyl", "heterocycloalkenyl " and "heteroaryl"
35 correspondingly, where the heteroatoms may be selected
from nitrogen, sulfur and oxygen. Examples of saturated
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heterocyclyl radicals include saturated 3 to 6-membered
heteromonocyclic group containing 1 to 4 nitrogen atoms
(e.g. pyrrolidinyl , imidazolidinyl , piperidino,
piperazinyl, etc.); saturated 3 to 6-membered
5 heteromonocyclic group containing 1 to 2 oxygen atoms and
1 to 3 nitrogen atoms (e.g. morpholinyl, etc.) ; saturated
3 to 6-membered heteromonocyclic group containing 1 to 2
sulfur atoms and 1 to 3 nitrogen atoms (e.g.,
thiazolidinyl , etc.) . Examples of partially unsaturated
10 heterocyclyl radicals include dihydrothiophene ,
dihydropyran, dihydrofuran and dihydrothiazole .
Heterocyclyl radicals may include a pentavalent nitrogen,
such as in tetrazolium and pyridinium radicals. The term
"heteroaryl" embraces unsaturated heterocyclyl radicals.
15 Examples of heteroaryl radicals include unsaturated 3 to
6 membered heteromonocyclic group containing 1 to 4
nitrogen atoms, for example, pyrrolyl , pyrrol inyl ,
imidazolyl , pyrazolyl, pyridyl, pyrimidyl , pyrazinyl,
pyridazinyl, triazolyl (e.g., 4H- 1 , 2 , 4 - triazolyl , 1H-
20 1 , 2 , 3 -triazolyl , 2H-1 , 2 , 3 -triazolyl , etc.) tetrazolyl
(e.g. 1H- tetrazolyl , 2H- tetrazolyl , etc.), etc.;
unsaturated condensed heterocyclyl group containing 1 to
5 nitrogen atoms, for example, indolyl , isoindolyl,
indolizinyl, benzimidazolyl , quinolyl, isoquinolyl,
25 indazolyl , benzotriazolyl , tetrazolopyridazinyl (e.g.,
tetrazolo [ 1 , 5 -b] pyridazinyl , etc.), etc.; unsaturated 3
to 6-membered heteromonocyclic group containing an oxygen
atom, for example, pyranyl , f uryl , etc.; unsaturated 3 to
6-membered heteromonocyclic group containing a sulfur
30 atom, for example, thienyl , etc.; unsaturated 3- to 6-
membered heteromonocyclic group containing 1 to 2 oxygen
atoms and 1 to 3 nitrogen atoms, for example, oxazolyl,
isoxazolyl, oxadiazolyl (e.g., 1 , 2 , 4 -oxadiazolyl , 1,3,4-
oxadiazolyl, 1 , 2 , 5 -oxadiazolyl , etc.) etc.; unsaturated
3 5 condensed heterocyclyl group containing 1 to 2 oxygen
atoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl ,
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benzoxadiazolyl , etc.); unsaturated 3 to 6-membered
heteromonocyclic group containing 1 to 2 sulfur atoms and
1 to 3 nitrogen atoms, for example, thiazolyl,
thiadiazolyl (e.g., 1,2,4- thiadiazolyl , 1,3,4-
5 thiadiazolyl, 1 , 2 , 5-thiadiazolyl , etc.) etc.; unsaturated
condensed heterocyclyl group containing 1 to 2 sulfur
atoms and 1 to 3 nitrogen atoms (e.g., benzothiazolyl ,
benzothiadiazolyl , etc.) and the like. The term
"heteroaryl" also embraces radicals where heterocyclyl
10 radicals are fused with aryl radicals. Examples of such
fused bicyclic radicals include benzofuran,
benzothiophene , and the like. Said heterocyclyl group
may have 1 to 3 substituents such as alkyl , hydroxyl ,
halo, alkoxy, oxo, amino and alkylamino. The term
15 "heterocyclylalkylene" embraces heterocyclyl-substituted
alkyl radicals. More preferred heterocyclylalkylene
radicals are "lower heterocyclylalkylene" radicals having
one to six carbon atoms and a heterocyclyl radical .
The term "alkylthio" embraces radicals containing a
2 0 linear or branched alkyl radical, of one to about ten
carbon atoms attached to a divalent sulfur atom. More
preferred alkylthio radicals are "lower alkylthio"
radicals having alkyl radicals of one to six carbon
atoms. Examples of such lower alkylthio radicals are
2 5 methyl thio, ethyl thio, propylthio, butyl thio and
hexylthio. The term "alkylthioalkylene " embraces
radicals containing an alkylthio radical attached through
the divalent sulfur atom to an alkyl radical of one to
about ten carbon atoms. More preferred alkylthioalkylene
3 0 radicals are "lower alkylthioalkylene" radicals having
alkyl radicals of one to six carbon atoms. Examples of
such lower alkylthioalkylene radicals include
methylthiomethyl . The term "alkylsulf inyl " embraces
radicals containing a linear or branched alkyl radical,
3 5 of one to about ten carbon atoms, attached to a divalent
-S(=0)- radical. More preferred alkylsulf inyl radicals
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are "lower alkylsulf inyl " radicals having alkyl radicals
of one to six carbon atoms. Examples of such lower
alkylsulf inyl radicals include methylsulf inyl ,
ethylsulf inyl , butylsulf inyl and hexylsul f inyl . The term
5 "sulfonyl", whether used alone or linked to other terms
such as " alkylsulf onyl " , or "halosulf onyl " denotes a
divalent radical, -S0 2 - . "Alkylsulf onyl " embraces alkyl
radicals attached to a sulfonyl radical, where alkyl is
defined as above. More preferred alkylsulf onyl radicals
10 are "lower alkylsulf onyl " radicals having one to six
carbon atoms. Examples of such lower alkylsulf onyl
radicals include methylsulf onyl , ethylsulf onyl and
propylsulf onyl . The " alkylsulf onyl " radicals may be
further substituted with one or more halo atoms, such as
15 fluoro, chloro or bromo, to provide haloalkylsulf onyl
radicals. The term "halosulf onyl " embraces halo radicals
attached to a sulfonyl radical. Examples of such
halosulfonyl radicals include chlorosulf onyl and
bromosulf onyl . The terms "sulfamyl", " aminosulf onyl " and
20 " sulf onamidyl " denote NH 2 0 2 S- .
The term "carbonyl", whether used alone or with
other terms, such as "alkoxycarbonyl " , denotes - (C=0) - .
The terms "carboxy" or "carboxyl", whether used alone or
with other terms, such as " carboxyalkyl " , denotes -C0 2 H.
25 The term "carboxyalkyl" embraces alkyl radicals
substituted with a carboxy radical . More preferred are
"lower carboxyalkyl" radicals which embrace carboxy -
substituted lower alkyl radicals, as defined above.
Examples of such lower carboxyalkyl radicals include
3 0 carboxymethyl , carboxyethyl and carboxypropyl . The term
"alkoxycarbonyl" means a radical containing an alkoxy
radical, as defined above, attached via an oxygen atom to
a carbonyl radical. More preferred are "lower
alkoxycarbonyl" radicals with alkyl portions having one
35 to six carbons. Examples of such lower alkoxycarbonyl
(ester) radicals include methoxycarbonyl , ethoxycarbonyl ,
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propoxycarbonyl , butoxycarbonyl and hexyloxycarbonyl .
The term "alkoxycarbonylalkylene " embraces alkyl radicals
substituted with an alkoxycarbonyl radical as defined
above. More preferred are "lower alkoxycarbonylalkylene"
5 radicals with alkyl portions having one to six carbons.
Examples of such lower alkoxycarbonylalkylene radicals
include methoxycarbonylmethylene ,
ethoxycarbonylmethylene , methoxycarbonyl ethylene and
ethoxycarbonylethylene . The term " alkyl carbonyl " ,
10 includes radicals having alkyl radicals attached to a
carbonyl radical . Examples of such radicals include
methyl carbonyl , ethyl carbonyl , propyl carbonyl ,
butylcarbonyl , and pentylcarbonyl . The term "aralkyl"
embraces aryl-substituted alkyl radicals. Preferred
15 aralkyl radicals are "lower aralkyl" , having lower alkyl
groups substituted with one or more aryl groups.
Examples of such groups include benzyl, diphenylmethyl ,
triphenylmethyl , phenylethyl, and diphenylethyl . The
aryl in said aralkyl may be additionally substituted with
2 0 halo, alkyl, alkoxy, haloalkyl and haloalkoxy. The terms
benzyl and phenylmethyl are interchangeable . The term
"heterocyclylalkylene" embraces saturated, partially
unsaturated and unsaturated heterocyclyl - substituted
alkyl radicals such as pyrrol idinylmethyl , pyridylmethyl ,
25 quinolylmethyl , thienylmethyl , furylethyl, and
quinolylethyl . The heteroaryl in heteroaralkyl
(unsaturated heterocyclyl -substituted alkyl radicals) may
be additionally substituted with halo, alkyl, alkoxy,
haloalkyl and haloalkoxy. The term "aryloxy" embraces
3 0 aryl radicals attached through an oxygen atom to other
radicals. The term "aralkoxy" embraces aralkyl radicals
attached through an oxygen atom to other radicals.
The term "aminoalkyl" embraces alkyl radicals
substituted with amino radicals. More preferred are
3 5 "lower aminoalkyl" radicals. Examples of such radicals
include aminomethyl , aminoethyl, and the like. The term
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"alkylamino" denotes amino groups which are substituted
with one or two alkyl radicals. Preferred are "lower
alkylamino" radicals having alkyl portions having one to
six carbon atoms. Suitable lower alkylamino may be
5 monosubst ituted N-alkylamino or disubst ituted N,N-
alkylamino, such as N-methylamino , N-ethylamino , N,N-
dimethyl amino, N, N-diethylamino or the like. The term
"arylamino" denotes amino groups which are substituted
with one or two aryl radicals, such as N -phenyl amino .
10 The "arylamino" radicals may be further substituted on
the aryl ring portion of the radical . The term
" aminocarbonyl " denotes an amide group of the formula -
C(=0)NH. The term " alkylaminocarbonyl " denotes an
aminocarbonyl group which has been substituted with one
15 or two alkyl radicals on the amino nitrogen atom.
Preferred are "N-alkylaminocarbonyl " and "N,N-
dialkylaminocarbonyl " radicals. More preferred are
"lower N-alkylaminocarbonyl" and "lower N, N-
dialkylaminocarbonyl " radicals with lower alkyl portions
20 as defined above. The term " aminocarbonylamino " embraces
radicals having one or more aminocarbonyl radicals
attached to an amino radical . The term
"alkylaminocarbonylamino" embraces radicals having one or
more alkyl radicals attached to an aminocarbonylamino
25 radical. Preferred are "lower alkylaminocarbonylamino"
radicals with lower alkyl portions as defined above. The
term "alkylcarbonylamino" embraces amino groups which are
substituted with one or more alkylcarbonyl radicals. More
preferred alkylcarbonylamino radicals are "lower
30 alkylcarbonylamino" having lower alkylcarbonyl radicals
as defined above attached to amino radicals. The term
" alkylaminoalkylene " embraces radicals having one or more
alkyl radicals attached to an aminoalkyl radical . The
term "alkylsulf onyl amino" embraces radicals having one or
35 more alkylsulf onyl radicals attached to an amino radical.
Preferred are "lower alkylsulf onyl amino" radicals with
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lower alkyl portions as defined above. The term
"aminosulf onyl amino" embraces radicals having one or more
aminosulf onyl radicals attached to an amino radical. The
term " alkylaminosulf onylamino" embraces radicals having
5 one or more alkyl radicals attached to an
aminosulf onylamino radical. Preferred are "lower
alkylaminosulf onylamino" radicals with lower alkyl
portions as defined above.
The additional terms used to describe the
10 substituents of the pyrazole ring and not specifically
defined herein are defined in a similar manner to that
illustrated in the above definitions. As above, more
preferred substituents are those containing "lower"
radicals. Unless otherwise defined to contrary, the term
15 "lower" as used in this application means that each alkyl
radical of a pyrazole ring substituent comprising one or
more alkyl radicals has one to about six carbon atoms;
each alkenyl radical of a pyrazole ring substituent
comprising one or more alkenyl radicals has two to about
20 six carbon atoms; each alkynyl radical of a pyrazole ring
substituent comprising one or more alkynyl radicals has
two to about six carbon atoms; each cycloalkyl or
cycloalkenyl radical of a pyrazole ring substituent
comprising one or more cycloalkyl and/or cycloalkenyl
25 radicals is a 3 to 8 membered ring cycloalkyl or
cycloalkenyl radical, respectively; each aryl radical of
a pyrazole ring substituent comprising one or more aryl
radicals is a monocyclic aryl radical; and each
heterocyclyl radical of a pyrazole ring substituent
3 0 comprising one or more heterocyclyl radicals is a 4-8
membered ring heterocyclyl .
The present invention comprises the tautomeric forms
of compounds of Formula I . As illustrated below, the
pyrazoles of Formula I and I' are magnetically and
35 structurally equivalent because of the prototropic
tautomeric nature of the hydrogen:
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23
The present invention also comprises compounds of
Formula I having one or more asymmetric carbons. It is
5 known to those skilled in the art that those pyrazoles of
the present invention having asymmetric carbon atoms may
exist in diastereomeric , racemic, or optically active
forms. All of these forms are contemplated within the
scope of this invention. More specifically, the present
10 invention includes enantiomers, diastereomers , racemic
mixtures, and other mixtures thereof.
The present invention comprises a pharmaceutical
composition for the treatment of a TNF mediated disorder,
a p38 kinase mediated disorder, inflammation, and/or
15 arthritis, comprising a therapeut ically-ef f ective amount
of a compound of Formula I, or a therapeut ically-
acceptable salt or tautomer thereof, in association with
at least one pharmaceutically-acceptable carrier,
adjuvant or diluent.
2 0 The present invention also comprises a therapeutic
method of treating a TNF mediated disorder, a p3 8 kinase
mediated disorder, inflammation and/or arthritis in a
subject, the method comprising treating a subject having
or susceptible to such disorder or condition with a
25 therapeutically-ef f ective amount of a compound of Formula
I
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24
wherein
R 1 is selected from hydrido, alkyl, cycloalkyl,
5 alkenyl , alkynyl, heterocyclyl , cycloalkylalkylene ,
haloalkyl , hydroxyalkyl , aralkyl, alkoxyalkyl,
mercaptoalkyl , alkylthioalkylene , amino, alkylamino,
arylamino, aminoalkyl , alkylaminoalkylene ,
heterocyclylalkylene , aminocarbonylalkylene , and
10 alkylaminocarbonylalkylene ; and
R 2 is selected from hydrido, alkyl, alkenyl, alkynyl,
heterocyclyl, haloalkyl, heterocyclylalkyl , amino,
alkylamino, aminoalkyl, alkoxy, alkylthio, carboxy,
alkoxycarbonyl , carboxyalkyl , aminocarbonylamino ,
15 alkylaminocarbonylamino , alkylsulf onyl , aminosulf onyl ,
alkyl sulf onyl amino, aminosulf onyl amino,
alkylaminosulf onylamino , and alkynylamino ; wherein the
heterocyclyl and heterocyclylalkyl groups are optionally
substituted with one or more radicals independently
20 selected from alkylthio, alkylsulf onyl , alkylsulf inyl ,
halo, alkyl, alkoxy, aryloxy, aralkoxy, heterocyclyl,
haloalkyl, amino, cyano, and hydroxy; and
Ar 1 is aryl optionally substituted with one or more
radicals independently selected from halo, alkyl,
25 alkenyl, alkynyl, alkoxy, alkenoxy, alkyldioxy,
alkylthio, alkylsulf inyl , alkylsulf onyl , amino,
aminocarbonyl , cyano, alkoxycarbonyl, formyl,
aminosulf onyl , alkylamino, nitro, arylamino,
alkylcarbonylamino , halosulf onyl , aminoalkyl, and
30 haloalkyl; and
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25
HetAr 2 is pyridinyl , pyrimidinyl or quinolinyl
optionally substituted with one or more radicals
independently selected from alkylthio, alkylsulf onyl ,
alkylsulf inyl , halo, alkyl, heterocyclyl , alkoxy,
5 aralkoxy, haloalkyl, amino, cyano, aralkyl, alkylamino,
cycloalkylamino , cycloalkenylamino, arylamino,
al kynyl amino , and aral kyl amino ; or
a pharmaceutically-acceptable salt or a tautomer
thereof .
10 Also included in the family of compounds of Formula
I are the pharmaceutically-acceptable salts thereof. The
term "pharmaceutically-acceptable salts" embraces salts
commonly used to form alkali metal salts and to form
addition salts of free acids or free bases. The nature
15 of the salt is not critical, provided that it is
pharmaceutically-acceptable. Suitable pharmaceutically-
acceptable acid addition salts of compounds of Formula I
may be prepared from an inorganic acid or from an organic
acid. Examples of such inorganic acids are hydrochloric,
2 0 hydrobromic, hydroiodic, nitric, carbonic, sulfuric and
phosphoric acid. Appropriate organic acids may be
selected from aliphatic, cycloaliphatic , aromatic,
araliphatic, heterocyclyl, carboxylic and sulfonic
classes of organic acids, example of which are formic,
25 acetic, propionic, succinic, glycolic, gluconic, lactic,
malic, tartaric, citric, ascorbic, glucuronic, maleic,
fumaric, pyruvic, aspartic, glutamic, benzoic,
anthranilic, mesylic, stearic, salicylic,
p-hydroxybenzoic , phenylacetic , mandelic, embonic
30 (pamoic) , methanesulf onic , ethanesulf onic ,
benzenesulf onic , pantothenic, toluenesulf onic , 2-
hydroxyethanesulf onic , sulf anilic ,
cyclohexylaminosulf onic , algenic, jS-hydroxybutyric ,
galactaric and galacturonic acid. Suitable
35 pharmaceutically-acceptable base addition salts of
compounds of Formula I include metallic salts and organic
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salts. More preferred metallic salts include, but are
not limited to appropriate alkali metal (group la) salts,
alkaline earth metal (group I la) salts and other
physiological acceptable metals. Such salts can be made
5 from aluminum, calcium, lithium, magnesium, potassium,
sodium and zinc . Preferred organic salts can be made from
tertiary amines and quaternary ammonium salts, including
in part, tromethamine , diethylamine , N, N' -
dibenzylethylenediamine , chloroprocaine , choline,
10 diethanolamine , ethyl enediamine , meglumine (N-
methylglucamine) and procaine. All of these salts may be
prepared by conventional means form the corresponding
compound of Formula I by reacting, for example, the
appropriate acid or base with the compound of Formula I .
15
General Synthetic Procedures
The compounds of the invention can be synthesized
according to the following procedures of Schemes I - VI
wherein the R 1 - R 3 substituents and Ar 1 , HetAr 2 are as
2 0 defined for Formula I, above, except where further noted.
Scheme I
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27
4
5
Scheme I shows the three step preparation of the
pyrazole 5 of the present invention. In step 1, the
5 reaction of arylmethyl derived ketone 1 with pyridine
derived aldehyde 2 either in a solvent such as benzene or
toluene in the presence of a base such as pyridine or in
a mixture of acids such as acetic acid and hydrogen
bromide gives the a, /3- unsaturated ketone 3. In step 2, in
10 the presence of base such as sodium hydroxide, o?,/6-
unsaturated ketone 3 is converted to the corresponding
epoxide 4 by the treatment with hydrogen peroxide
solution at room temperature. In step 3, epoxide 4 is
condensed with hydrazine in a suitable solvent such as
15 ethanol at temperature ranging up to the boiling point to
form pyrazole 5. Alternatively, pyrazole 5 can be
prepared by treatment of 3 with tosyl hydrazide in the
presence of an acid such as acetic acid at reflux.
20
Scheme II
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28
route 3
1 0
0 ° C
heat C180' > -200°C;)
. N H ,
25 <
■ 200° C
10
15
1 2
Scheme II shows the synthesis of pyrazole 12
containing a heteroaromatic ring by three routes . In
Route 1, ketone 6 is condensed with hydrazine 7 to give
substituted hydrazine 9, which is then reacted with acyl
halide or anhydride 10 at low temperature to provide acyl
hydrazone 11. Upon heating at temperature up to 200 °C,
hydrazone 11 is converted to pyrazole 12. In Route 2,
acyl hydrazone 11 is formed directly by reaction of
ketone 6 with acyl hydrazide 8 at room temperature. Acyl
hydrazide 8 may be formed by reaction of hydrazine with a
carboxylic acid ester. Heating 11 as above then provides
pyrazole 12. In Route 3, ketone 6 is treated with acyl
hydrazide 8 at from room temperature to ~2 0 0 °C to give
pyrazole 12 directly. Alternatively, this condensation
may be carried out in an acidic solvent, such as acetic
acid, or in a solvent containing acetic acid.
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1 5
Cyanoketone 13 may be synthesized according to the
procedure described by I . Lantos et al in J . Org . Chem. ,
5 volume 53, pp. 4223-4227 (1988) for the synthesis of the
p-fluoro compound (X = p-F) . This procedure, which is
incorporated herein by reference, can be used to
synthesize cyanoketones such as 13 wherein X is selected
from, for example, halogen, alkyl and alkoxy.
10 Cyanoketones such as 13 may be converted to pyrazoles 14
by reaction with a hydrazine in a suitable solvent, such
as benzene or toluene. A catalyst such as acetic acid
may be employed. When hydrazine itself is employed, the
ring nitrogen atoms of the pyrazole thus obtained bear no
15 substituent except hydrogen on one of the ring nitrogen
atoms. When a substituted hydrazine, such as
methylhydrazine is employed, the product pyrazole 14
bears a substituent on the ring nitrogen atom adjacent to
the aminated ring carbon atom, as shown in Scheme 1 . The
2 0 resultant aminopyrazole 14 may be acylated or
sulfonylated to form substituted aminopyrazole 15 by
treatment with a suitably activated carboxylic or
sulfonic acid in a suitable solvent such as pyridine.
Examples of a suitably activated carboxylic acid include
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acetic anhydride or benzoyl chloride. Examples of a
suitably activated sulfonic acid include methanesulf onyl
chloride, p- toluenesulf onyl chloride or sulfamyl
chloride .
di methy Iforrnamide
dimethyl acetal
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Scheme IV illustrates the synthesis of 3 -pyridyl -4 -
aryl -pyrazoles of the present invention. Benzoate 16 is
first reacted with pyridine 17 in the presence of a base,
such as an alkali metal alkoxide (preferably sodium
5 methoxide) , in a suitable solvent, such as
tetrahydrof uran . Subsequent treatment with an acid,
preferably a mineral acid such as hydrochloric acid,
yields the desoxybenzoin 18. Desoxybenzoin 18 is then
converted to ketone 19 by treatment with an excess of
10 dimethyl formamide dimethyl acetal . Ketone 19 is then
reacted with hydrazine in a suitable solvent such as
ethanol to yield a mixture of pyrazoles 2 0 and 21. In
Scheme IV, R 4 represents one or more radicals
independently selected from the optional substituents
15 previously defined for Ar 1 ; and R 5 represents one or more
radicals independently selected from the optional
substituents previously defined for HetAr 2 .
The 3-pyrimidinyl-4-aryl-pyrazoles of the present
invention can be synthesized in the manner of Scheme IV
20 by replacing pyridine 17 with the corresponding
pyrimidine .
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In Scheme V, hydroxyalkyl pyrazoles 22 and 23 are
5 converted to sulfonate derivatives by reaction with an
alkyl- or arylsulfonyl halide. These sulfonates are then
reacted with ammonia or primary amines or secondary
amines to give the corresponding 1-amino-pyrazoles 24 and
25, respectively. In Scheme V, n is 1, 2, 3, 4 or 5; R 4
10 and R 5 are as defined in Scheme IV; R 6 and R 7 are
independently selected, for example, from hydrogen, alkyl
and aryl , or together with the nitrogen atom to which
they are attached form a 4-8 membered ring that may
contain one or more additional heteroatoms selected from
15 oxygen, nitrogen or sulfur.
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Scheme VI
o
1 8
NH 2 - NHR 1
2 0 26
5 Scheme VI is similar to Scheme IV except that
desoxybenzoin 18 is first reacted with hydrazine in a
suitable solvent such as ethanol to yield hydrazine 26.
Hydrazine 26 is then converted to pyrazole 20 (rather
than a mixture of pyrazoles 20 and 21 as in Scheme IV) by
10 treatment with an excess of dimethyl formamide dimethyl
acetal . In Scheme VI, R 4 and R 5 are as defined in Scheme
V.
The following examples contain detailed descriptions
of the methods of preparation of compounds of Formula I.
15 These detailed descriptions fall within the scope, and
serve to exemplify, the above described General Synthetic
Procedures which form part of the invention. These
detailed descriptions are presented for illustrative
purposes only and are not intended as a restriction on
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the scope of the invention. All parts are by weight and
temperatures are in Degrees centigrade unless otherwise
indicated. All compounds showed NMR spectra consistent
with their assigned structures. In some cases, the
5 assigned structures were confirmed by nuclear Overhauser
effect (NOE) experiments.
The following abbreviations are used:
HC1 - hydrochloric acid
MgS0 4 - magnesium sulfate
10 Na 2 S0 4 - sodium sulfate
NaI0 4 - sodium periodate
NaHS0 3 - sodium bisulfite
NaOH - sodium hydroxide
KOH - potassium hydroxide
15 P2°5~ phosphorus pent oxide
MeOH - methanol
EtOH - ethanol
HOAc (or AcOH) - acetic acid
EtOAc - ethyl acetate
2 0 H z O - water
H 2 O z 2 _ hydrogen peroxide
CH 2 C1 2 - methylene chloride
NaOMe - sodium methoxide
h - hour
2 5 hr - hour
min - minutes
THF - tetrahydrof uran
TLC - thin layer chromatography
DSC - differential scanning calorimetry
3 0 b.p. - boiling point
m.p. - melting point
eq - equivalent
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EXAMPLE 1
4- (3-methyl-4-phenyl-lH-pyrazol-5-yl) pyridine
5
Step 1: Preparation of 3 -phenyl -4 - (4 -pyridyl ) -3 -butene-
2 - one
3 -Phenyl-4 - (4 -pyridyl ) -3 -butene-2 -one was prepared by the
method of Reichert and Lechner, Arzneim. -Forsch. 15, 36
10 (1965) , which is incorporated by reference herein.
Step 2: Preparation of 3 -phenyl -4 - (4 -pyridyl ) - 3 , 4 -epoxy-
2 -butanone
To a stirred solution of 3 -phenyl-4- (4 -pyridyl) -3-
15 butene-2 -one (step 1) (500 mg, 2.2 4 mmol) in methanol (10
ml) at room temperature was added an aqueous solution (9
ml) of sodium hydroxide (100 mg, 2.24 mmol) and hydrogen
peroxide (0.5 ml of 3 0% aqueous solution, 4.4 mmol) .
After stirring for 2 hours, sodium chloride was added and
2 0 the reaction was extracted with ethyl acetate. The
combined organic layers were dried over magnesium
sulfate, filtered, and concentrated in vacuo to provide
the crude 3 -phenyl-4 - (4 -pyridyl ) -3 , 4 -epoxy-2 -butanone
(385 mg, 65%) as an oil. This was used in the next step
2 5 without further purification.
Step 3: Preparation of 4 - ( 3 -methyl -4 -phenyl -lH-pyrazol -
5 -yl ) pyridine
A solution of 3 -phenyl -4 - (4 -pyridyl )- 3 , 4 -epoxy-2 -
3 0 butanone (step 2) (3 50 mg, 1.4 6 mmol) and anhydrous
hydrazine (0.7 ml, 2 0 mmol) in ethanol (3 ml) was heated
at reflux for 4 hours. The reaction was cooled, and the
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solvent was evaporated to dryness. The resulting residue
was purified by chromatography (silica gel, 1:1
acetone/hexane) to give the desired product as a
crystalline solid, which was recrystallized from ethyl
5 acetate and hexane to give pure 4- ( 3 -methyl -4 -phenyl -1H-
pyrazol- 5 -yl) pyridine (145 mg, 42%): m. p. 164-165°C.
Anal. Calc'd for C 15 H 13 N 3 (235.29): C, 76.57; H, 5.57; N,
17.86. Found: C, 76.49; H, 5.45; N, 17.70.
The compounds of Examples 2 through 8 were
10 synthesized in accordance with the chemistry described
above (particularly in Scheme III) by selection of the
corresponding starting reagents:
EXAMPLE 2
15
4- (4-f luorophenyl) -5- ( 4 -pyridinyl ) - lH-pyrazol - 3 -amine
The cyanoketone 1 of Scheme III wherein X is p-
20 fluoro was synthesized according to the procedure of I.
Lantos et al . , J. Org. Chem. , 53, 4223-4227 (1988), which
is incorporated herein by reference. A solution of the
cyanoketone (10 g, 41 mmol) , hydrazine hydrate (2.5 ml)
and acetic acid (5.2 ml) in benzene (100 ml) was refluxed
25 for 4 hours. The reaction was cooled and extracted with
3N HCl . The combined acid extracts were basified to pH
10 using concentrated ammonium hydroxide with cooling.
The basic aqueous layer was extracted with methylene
chloride and the combined organic extracts were dried
3 0 over magnesium sulfate.
The drying agent was filtered and the filtrate
concentrated in vacuo to give the crude 4- (4-
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f luorophenyl ) -5- (4 -pyridinyl ) - lH-pyrazol -3 -amine which
was purified by recrystallizat ion from ethyl acetate and
hexane . Purified 4- (4- f luorophenyl) -5- (4-pyridinyl) -1H-
pyrazol-3 -amine had m.p. 178-180°C (capillary) .
5 Anal. Calc'd for C 14 H n N 4 F + 0.25 H 2 0 : C, 64.99; H,
4.48; N, 21.65. Found: C, 64.99; H, 4.48; N, 21.54.
EXAMPLE 3
10
N- [4 (4 -f luorophenyl) -5- (4 -pyridinyl ) -lH-pyrazol-
3 -yl] methanesulf onamide
A solution of 4 - (4 - f luorophenyl )- 5 - (4 -pyridinyl )- 1H-
pyrazol-3 -amine prepared as set forth in Example 2 (200
15 mg, 0.77 mmol) and methanesulf onyl chloride (90 mg) in
pyridine (5 ml) was stirred at room temperature
overnight . The pyridine was removed in vacuo and the
residue was treated with methylene chloride and water.
The resultant precipitate was filtered to give N-[4(4-
20 f luorophenyl ) -5- ( 4 -pyridinyl ) - lH-pyrazol -3 -
yl ] methanesulf onamide . Additional N- [4 (4 -f luorophenyl) -
5- (4-pyridinyl) - lH-pyrazol -3 -yl ] methanesulf onamide was
contained in the methylene chloride layer. The methylene
chloride was stripped in vacuo and the residue purified
25 by chromatography on silica gel using mixtures of ethyl
acetate and methanol as eluents. The purified N- [4 (4-
f luorophenyl ) -5- (4-pyridinyl) - lH-pyrazol -3 -
yl] methanesulf onamide had m.p. 168-170°C.
Anal. Calc'd for C 15 H 13 N 4 S0 2 F + 0.25 H 2 0 : C, 53.48; H,
30 4.04; N, 16.63. Found: C, 53.41; H, 3.78; N, 16.52.
EXAMPLE 4
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N- [4- (4-f luorophenyl) -5- (4 -pyridinyl ) - IH-pyrazol - 3 -
yl] -N' -methylsulf amide
5 Methyl sulfamyl chloride was synthesized by
refluxing a solution of methylsulf ami c acid (1.0 g) in
phosphorus oxychloride (10 mL) for 6 hours. The excess
phosphorus oxychloride was removed in vacuo and the
residual oil was used for the synthesis of the product
10 without further treatment. A solution of 4- (4-
f luorophenyl ) -5- (4 -pyridinyl) -lH-pyrazol-3-amine prepared
as set forth in Example 2 (200 mg, 0.77 mmol) and
approximately 1 mmol of the above oil in pyridine (5 ml)
was stirred at room temperature for 2 hours. The
15 reaction was stripped in vacuo and the residue purified
by chromatography on silica gel using ethyl acetate and
mixtures of ethyl acetate and methanol as eluents to give
N- [4- (4-f luorophenyl) -5- ( 4 -pyridinyl ) -IH-pyrazol -3 -1-yl] -
N' -methylsulf amide as a crystalline solid, m. p. 194-
20 195°C.
Anal. Calc'd for C 15 H 14 N 5 S0 2 F + 1.0 H 2 0 : C, 4 9.31; H,
4.41; N, 19.17. Found: C, 49.13; H, 3.97; N, 19.01.
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N H 2
[4- (4-f luorophenyl) -5- (4-pyridinyl) -lH-pyrazol-3-yl] urea
5 A suspension of 4- (4-f luorophenyl) -5- (4 -pyridinyl ) -
lH-pyrazol -3 -amine prepared as set forth in Example 2
(200 mg, 0.77 mmol) in a solution of di-tert-butyl
carbonate (185 mg, 0.9 mmol) and 4 -dimethyl aminopyri dine
(DMAP) (10 mg) in methylene chloride (10 ml) was stirred
10 at room temperature for 2 0 minutes, during which time,
the suspended material dissolved. N-Propylamine (50 mg)
was added and stirring was continued at room temperature
for 1 hour. The reaction was then refluxed for 15
minutes, cooled and stripped in vacuo. Treatment with
15 ethyl acetate and hexane resulted in the deposition of
crystals of the tert -butoxycarbonyl derivative, m.p. 183-
184°C.
Anal. Calc'd for C 19 H 19 N 4 0 2 F: C, 64.4 0; H, 5.4 0; N,
15.81. Found: C, 64.66; H, 5.63; N, 15.63.
2 0 A solution of the tert -butoxycarbonyl derivative
above (100 mg, 0.3 mmol) in tetrahydrof uran was treated
with ammonia at 80°C in a pressure bottle for 12 hours.
The reaction was stripped in vacuo and the residue was
purified by chromatography on silica gel eluting with
25 mixtures of ethyl acetate and methanol. The purified [4-
(4 -f luorophenyl) -5- (4-pyridinyl) -lH-pyrazol-3-yl] urea
thus obtained had m.p. 224-225°C.
Anal. Calc'd for C 15 H 12 N 5 0 : C, 60.60; H, 4.07; N,
23.56. Found: C, 60.21; H, 4.11; N, 23.30.
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EXAMPLE 6
[4- (4 -f luorophenyl) -5- (4-pyridinyl) - lH-pyrazol -3 -
5 yl] sulf amide
Sulfamyl chloride was synthesized from
chlorosulf onyl isocyanate according to the procedure
described by R. Graf in Chemische Berichte , p. 509
(1959), which is incorporated herein by reference. A
10 solution of 4 - (4 -f luorophenyl ) -5 - (4 -pyridinyl ) - 1H-
pyrazol-3-amine prepared as set forth in Example 2 (2 00
mg, 0.77 mmol), sulfamyl chloride (100 mg, 0.8 mmol) and
triethylamine (2 00 mg, 2 mmol) in benzene (5 ml) and
acetonitrile (5 ml) was stirred at room temperature for 2
15 hours. The reaction was stripped in vacuo and residue
was treated with water and basified to pH 7 with ammonium
hydroxide. The resultant precipitate was purified by
chromatography on silica gel using mixtures of ethyl
acetate and methanol as eluents. The purified [4- (4-
20 f luorophenyl ) -5- (4-pyridinyl) - lH-pyrazol -3 -yl ] sulfamide
thus obtained had m.p. 201-202°C.
Anal. Calc'd for C 14 H 12 N 5 S0 2 F : C, 50.44; H, 3.63; N,
21.01. Found: C, 50.43; H, 3.45; N, 20.89.
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EXAMPLE 7
c I
5 4- (4 -chlorophenyl) - 1 -methyl -3 - (4 -pyridinyl ) -1H-
pyrazol-5-amine
A solution of cyanoketone 1 of Scheme III wherein X
is p-chloro (1.5 g, 5.19 mmol) , methylhydrazine (0.35 ml)
and acetic acid (0.75 ml) in benzene (15 ml) was refluxed
10 for 3.5 hours. The reaction was cooled and extracted
with 3N HC1 . The aqueous layer was concentrated on the
rotary evaporator and then basified with ammonium
hydroxide. The resultant precipitate was recrystallized
from methanol to give pure 4- (4 -chlorophenyl) -l-methyl-3-
15 (4 -pyridinyl) -lH-pyrazol-5-amine, m.p. 257-258°C.
Anal. Calc'd for C 15 H 13 N 4 C1 : C, 63.27; H, 4.60; N,
19.68. Found: C, 62.93; H, 4.45; N, 19.64.
EXAMPLE 8
N- [4- (4-f luorophenyl) -5- (4 -pyridinyl ) -lH-pyrazol-3-
yl] -N ' -methylurea
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A solution of 4- (4-f luorophenyl) -5- (4 -pyridinyl ) -1H-
pyrazol-3-amine prepared as set forth in Example 2 (10 0
mg, 0.38 mmol), methyl isocyanate (22 mg, 0.39 mmol) and
4 -dimethylaminopyridine (2.5 mg) in methylene chloride
5 (10 ml) was stirred at room temperature for 30 minutes.
The reaction was stripped in vacuo. The residue was
triturated with hexane and the solid filtered to give
pure N- [4- (4 - f luorophenyl ) -5- (4 -pyridinyl ) - lH-pyrazol - 3 -
yl] -N' -methylurea, m. p. 212-213°C.
10 Anal. Calc'd for C 16 H 14 N 5 FO : C, 61.73; H, 4.53; N,
22.50. Found: C, 61.63; H, 4.55; N, 22.47.
The compounds of Examples 9 through 11 were
synthesized in accordance with the chemistry described
above (particularly in Scheme IV) by selection of the
15 corresponding starting reagents:
EXAMPLE 9
4- [4- (4 - f luorophenyl ) - lH-pyrazol -3 -yl ] pyridine
20
Step 1
Methyl isonicotinate (13. 7g, O.lmole) and ethyl 4-
f luorophenylacetate (18. 2g, O.lmole) were mixed together,
then sodium methoxide (8.1g, O.lSmole) was added. The
25 mixture was heated to 60-70°C for 24 hours while nitrogen
was blown through the flask to eliminate methanol.
Concentrated hydrochloric acid (50 mL) then was added and
the reaction mixture was refluxed for 3 hours. After
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addition of water (3 0 mL) , the reaction mixture was
extracted with chloroform, and the water phase was
neutralized to pH 6 - 7 with aqueous sodium hydroxide
(1M) . The precipitate formed was collected by
5 filtration, washed with water and dried under vacuum to
give 10 g of 2- (4 -f luorophenyl) -1- (4 ' -pyridyl) -ethan-1-
one (yield: 46%) . 1 H NMR: consistent with the assigned
structure and/or its tautoraer.
10 Step 2
2- (4 -f luorophenyl) -1- (4' -pyridyl) -ethan-l-one
prepared above (1 g) was dissolved in 5 0 mL
tetrahydrof uran and N, N- dimethyl formamide dimethyl acetal
(5 mL) was added. The mixture was stirred at room
15 temperature for 2 days. After evaporating the solvent,
the solid obtained was washed with hexane and 1 g of the
vinyl amine was obtained. This vinyl amine (0.5 g) was
dissolved in ethanol (15 mL) and hydrazine hydrate (5 mL)
was added. The mixture was stirred at 0°C for 2 hours and
20 then evaporated to dryness. After recrystallization from
methanol /water, 400 mg of 4 - [4 - (4 - f luorophenyl )- 1H-
pyrazol - 3 -yl] pyridine was obtained in 91% yield. MS,
240 (M+l) ; 1 H NMR: consistent with the assigned structure;
Anal. Calc'd for C 14 H 10 FN 3 . 0 . 2H 2 0 : C, 69.24; H, 4.32; N,
25 17.30. Found: C, 69.54; H, 4.06; N, 17.43.
EXAMPLE 10
4- [4- (4 -f luorophenyl) - 1 -methyl - lH-pyrazol -3 -yl] pyridine
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When methyl hydrazine was substituted for hydrazine
hydrate in Step 2 of Example 9, 4 - [4 - (4 -fluorophenyl )- 1 -
methyl -lH-pyrazol- 3 -yl] pyridine (the N-methyl derivative
corresponding to the compound of Example 9) was obtained.
5 Purification by recrystallizat ion from toluene and hexane
give the pure 4 - [4 - (4 - fluorophenyl )- 1 -methyl - lH-pyrazol -
3-yl] pyridine in 57% yield. MS m/z: 254 (M+l). X H NMR :
consistent with the assigned structure. Anal, calc'd for
C 15 H 12 FN 3 : C, 71.13; H, 4.78; N, 16.69. Found: C, 70.99; H,
10 4.68; N, 16.65.
EXAMPLE 11
OH
4- (4 -f luorophenyl) -3- (4 -pyridinyl ) -lH-pyrazole-l-ethanol
15 and
4- (4 -f luorophenyl) -5- (4 -pyridinyl ) -lH-pyrazole- 1-ethanol
The procedure set forth in Example 9 was followed
except that 2 - hydroxy ethyl hydrazine was substituted for
20 hydrazine hydrate. 4 - (4 -Fluorophenyl ) -3 - (4 -pyridinyl ) -
lH-pyrazole-l-ethanol and 4- (4 -fluorophenyl) -5- (4-
pyridinyl )- lH-pyrazole- 1 -ethanol were obtained as a
mixture by recrystallization from toluene and hexane in
67% yield. 1 H NMR: consistent with the assigned structure.
25 Mass spectrum, m/z: 284 (M+l) . Anal, calc'd for C 16 H 14 FN 3 0 :
C, 67.83; H, 4.98; N, 14.83. Found: C, 67.86; H, 5.04; N,
14 . 85 .
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The compounds of Examples 12 and 13 were synthesized
in accordance with the chemistry described above
(particularly in Scheme V) by selection of the
corresponding starting reagents:
5
EXAMPLE 12
4- (4-f luorophenyl) -N, N-dimethyl -3 - (4 -pyridinyl ) -1H-
pyrazole- 1-ethanamine
10 and
4- (4-f luorophenyl) -N, N-dimethyl -5- (4 -pyridinyl ) -1H-
pyrazole- 1-ethanamine
4- (4 -Fluorophenyl ) -3- ( 4 -pyridinyl ) - lH-pyrazole- 1 -ethanol
15 (or 4 - (4 - fluorophenyl )- 5 - (4 -pyridinyl )- lH-pyrazole- 1 -
ethanol) prepared as set forth in Example 11 (1.36 g) was
dissolved in 3 0 mL pyridine and cooled to 0°C, whereupon
methanesulf onyl chloride (0.6 mL) was added. After
stirring at 0°C for 12 hours, about 20 g of ice was
2 0 added, and the mixture was extracted with toluene (3 0 0
ml) . After evaporation, the residue was used directly
without further purification. 0.7 g of the above
obtained compound was dissolved in methanol (25 mL) , and
dimethylamine/THF solution (4M, 2 mL) was added. The
25 reaction mixture was refluxed for 12 hours, then
evaporated to dryness. The residue was purified by
chromatography (methanol /dichloromethane 1:10) . A
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mixture (0.59 g) of 4- (4 - f luorophenyl ) -N, N- dimethyl -3 - (4-
pyridinyl) - 1H -pyrazol e - 1 - ethanamine and 4- (4-
f luorophenyl ) -N,N-dimethyl-5- (4 -pyridinyl ) -lH-pyrazole-1-
ethanamine were obtained. 1 H NMR: consistent with the
5 assigned structure. Mass spectrum, m/ z : 311 (M+l) . Anal,
calc'd C 18 H 19 N 4 F.0.55H 2 O: C, 67.50; H, 6.33; N, 17.49.
Found: C, 67.21; H, 6.46; N, 17.14.
EXAMPLE 13
10
4- [2- [4- (4 -f luorophenyl) -3- (4 -pyridinyl ) - lH-pyrazol - 1 -
yl] ethyl] morpholine
and
4- [2- [4- (4 -f luorophenyl) -5- (4 -pyridinyl ) - lH-pyrazol - 1 -
15 yl] ethyl] morpholine
The procedure set forth in Example 11 was followed,
except that morpholine was substituted for dimethylamine ,
to produce a mixture of 4 - [2 - [4 - (4 - f luorophenyl ) -3 - (4 -
20 pyridinyl) -lH-pyrazol-l-yl] ethyl] morpholine and 4- [2- [4-
(4 - f luorophenyl ) -5- ( 4 -pyridinyl ) - lH-pyrazol - 1 -
yl] ethyl] morpholine . Mass spectrum, m/ z : 353 (M+l).
Anal, calc'd for C 20 H 21 N 4 OF + 0 . 5H z O : C, 66.47; H, 6.14; N,
15.50. Found: C, 66.57; H, 6.27; N, 15.14.
25
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The compound of Example 14 was synthesized in
accordance with the chemistry described above
(particularly in Scheme VI) by selection of the
corresponding starting reagents :
EXAMPLE 14
4- [4- (4 -f luorophenyl ) - 1 -methyl - lH-pyrazol -3 -yl ] pyridine
10
2- (4 -f luorophenyl) -1- (4' -pyridyl) -ethan-l-one
prepared as set forth in step 1 of Example 9 (0.5 g,
0.00232 moles) was mixed with of 98% methyl hydrazine
(0.2 g, 0.00462 moles) in 10 mL of ethanol containing 0.1
15 mL of acetic acid in a 50 mL Erlenmeyer flask. After
gentle boiling (3 0 minutes on a steam bath) a small
sample was evacuated at high vacuum and examined by NMR
to confirm completion of hydrazone formation. The
reaction mixture was concentrated to a pasty mass and 3.6
20 mL of DMF dimethylacetal (0.027 moles) was then added and
heated to 80°C for 30 minutes, at which point a clear
yellow viscous solution was obtained. The reaction was
checked for completion (TLC or NMR) and concentrated and
taken up in 2 0 mL of chloroform. After washing with
2 5 water (10 mL) , the organic layer was extracted with 15 mL
of 10 % HC1 . The water layer was then treated with 0.5 g
of activated charcoal at 70 °C for 10 minutes, filtered
through celite, neutralized cautiously to pH 7-8 with
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vigorous stirring and cooling. The fine off-white
precipitate was filtered and dried. NMR was found to be
in agreement with the proposed structure. The
precipitate, 4- [4- {4-f luorophenyl) - 1 -methyl - lH-pyrazol - 3 -
5 yl] pyridine, obtained in quantitative yield was filtered,
washed with ether and dried. Yield: 0.45 g (77%) . Mass
spectrum, m/z: 254. Anal, calc'd: C, 62.18; H, 4.52; N,
14.50. Found: C, 62.39; H, 4.07; N, 14.24.
10 EXAMPLE 15
4 - [4 - (4 -chlorophenyl ) - lH-pyrazol -3 -yl ] pyridine
15 4 - [4 - (4 -chlorophenyl) - lH-pyrazol -3 -yl] pyridine was
prepared according to the procedure set forth in Example
9 except that ethyl 4 -chlorophenylacetate was substituted
for ethyl 4-f luorophenylacetate ; m.p. 204-207°C.
20 Anal. Calc'd: C, 65.76; H, 3.94; N, 16.43. Found: C,
65.44; H, 3.78; N, 16.04.
EXAMPLE 16
4 - (4 -phenyl - lH-pyrazol - 5 -yl ) pyridine
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4- (4 -phenyl -lH-pyrazol- 5 -yl) pyridine can be prepared
in accordance with the procedure set forth in Example 9
by substituting ethylphenylacetate for ethyl 4-
f luorophenylacetate .
5
EXAMPLE 17
10 1 -methyl -4- [2- [4- (4 - f luorophenyl ) -3- (4 -pyridinyl ) -1H-
pyrazol-l-yl] ] piperidine
and
l-methyl-4- [2- [4- (4 - f luorophenyl ) -5- ( 4 -pyridinyl ) -1H-
pyrazol-l-yl] piperidine
15
This compound can be prepared using the procedure
set forth for the synthesis of the compound of Example 11
by substituting 4 -hydrazino-N-methylpiperidine for
hydroxyethyl hydrazine. 4 -Hydrazino-N-methylpiperidine
20 is synthesized as disclosed in Ebnoether et al , Helv.
Chim. Acta (1959) 42, 533, 541, 560. The resulting
mixture is separated into the respective pure title
compounds by chromatography on silica gel, eluting with
methanol/dichloromethane (1:10), or other suitable
25 solvent system.
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50
BIOLOGICAL EVALUATION
p3 8 Kinase Assay
5 Cloning of human p38a:
The coding region of the human p3 8a cDNA was
obtained by PCR-amplif ication from RNA isolated from the
human monocyte cell line THP . 1 . First strand cDNA was
synthesized from total RNA as follows: 2 /ig of RNA was
10 annealed to 100 ng of random hexamer primers in a 10 /il
reaction by heating to 70 °C for 10 minutes followed by 2
minutes on ice. cDNA was then synthesized by adding 1 /il
of RNAsin (Promega, Madison WI), 2 /il of 50 mM dNTP's, 4
/il of 5X buffer, 2 /il of 100 mM DTT and 1 /il (200 U) of
15 Superscript II ™ AMV reverse transcriptase. Random
primer, dNTP's and Superscript ™ reagents were all
purchased from Life-Technologies, Gaithersburg , MA. The
reaction was incubated at 42 °C for 1 hour.
Amplification of p3 8 cDNA was performed by aliquoting 5
20 /il of the reverse transcriptase reaction into a 100 /il
PCR reaction containing the following: 80 /il dH 2 0, 2 /il
5 0 mM dNTP's, 1 /il each of forward and reverse primers
(50 pmol//il) , 10 /il of 10X buffer and 1 /il Expand ™
polymerase (Boehringer Mannheim) . The PCR primers
25 incorporated Bam HI sites onto the 5' and 3' end of the
amplified fragment, and were purchased from Genosys . The
sequences of the forward and reverse primers were 5'-
GATCGAGGATTCATGTCTCAGGAGAGGCCCA-3 ' and
5 ' GATCGAGGATTCTCAGGACTCCATCTCTTC- 3 ' respectively . The
30 PCR amplification was carried out in a DNA Thermal Cycler
(Perkin Elmer) by repeating 30 cycles of 94 °C for 1
minute, 6 0 °C f° r 1 minute and 6 8 °C for 2 minutes.
After amplification, excess primers and unincorporated
dNTP's were removed from the amplified fragment with a
35 Wizard ™ PCR prep (Promega) and digested with Bam HI
(New England Biolabs) . The Bam HI digested fragment was
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ligated into BamHI digested pGEX 2T plasmid DNA
(PharmaciaBiotech) using T-4 DNA ligase (New England
Biolabs) as described by T. Maniatis, Molecular Cloning :
A Laboratory Manual, 2nd ed. (1989) . The ligation
5 reaction was transformed into chemically competent E.
coll DH10B cells purchased from Life-Technologies
following the manufacturer's instructions. Plasmid DNA
was isolated from the resulting bacterial colonies using
a Promega Wizard™ miniprep kit. Plasmids containing the
10 appropriate Bam HI fragment were sequenced in a DNA
Thermal Cycler (Perkin Elmer) with Prism™ (Applied
Biosystems Inc.) . cDNA clones were identified that coded
for both human p38a isoforms (Lee et al . Nature 372,
73 9) . One of the clones which contained the cDNA for
15 p38a-2 (CSBP-2) inserted in the cloning site of pGEX 2T,
3' of the GST coding region was designated pMON 35802.
The sequence obtained for this clone is an exact match of
the cDNA clone reported by Lee et al . This expression
plasmid allows for the production of a GST-p38a fusion
20 protein.
Expression of human p3 8a:
GST/p38a fusion protein was expressed from the
plasmid pMON 35802 in E . coli , stain DH10B (Life
25 Technologies, Gibco-BRL) . Overnight cultures were grown
in Luria Broth (LB) containing 100 mg/ml ampicillin. The
next day, 500 ml of fresh LB was inoculated with 10 ml of
overnight culture, and grown in a 2 liter flask at 37 °C
with constant shaking until the culture reached an
30 absorbance of 0.8 at 600 nm. Expression of the fusion
protein was induced by addition of isopropyl b-D-
thiogalactosidse (IPTG) to a final concentration of 0.05
mM. The cultures were shaken for three hours at room
temperature, and the cells were harvested by
35 centrif ugation . The cell pellets were stored frozen
until protein purification.
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Purification of p38 Kinase-ct:
All chemicals were from Sigma Chemical Co. unless
noted. Twenty grams of E. coli cell pellet collected
from five 1 L shake flask fermentations was resuspended
5 in a volume of PBS (14 0 mM NaCl , 2.7 mM KC1 , 10 mM
Na 2 HP0 4 , 1.8 mM KH 2 P0 4# pH 7.3) up to 200 ml. The cell
suspension was adjusted to 5 mM DTT with 2 M DTT and then
split equally into five 50 ml Falcon conical tubes. The
cells were sonnicated (Ultrasonics model W375) with a 1
10 cm probe for 3X1 minutes (pulsed) on ice. Lysed cell
material was removed by centrif ugat ion (12,000 x g, 15
minutes) and the clarified supernatant applied to
glutathione -sepharose resin (Pharmacia) .
15 Glutathione- Sepharose Affinity Chromatography:
Twelve ml of a 50% glutathione sepharose-PBS
suspension was added to 200 ml clarified supernatant and
incubated batchwise for 3 0 minutes at room temperature.
The resin was collected by centrif ugat ion (600 x g, 5
20 min) and washed with 2 x 150 ml PBS/1% Triton X-100,
followed by 4 x 40 ml PBS. To cleave the p3 8 kinase from
the GST-p38 fusion protein, the glutathione-sepharose
resin was resuspended in 6 ml PBS containing 250 units
thrombin protease (Pharmacia, specific activity > 7500
25 units/mg) and mixed gently for 4 hours at room
temperature. The glutathione-sepharose resin was removed
by centrif ugation (600 x g, 5 min) and washed 2 x 6 ml
with PBS. The PBS wash fractions and digest supernatant
containing p38 kinase protein were pooled and adjusted to
3 0 0 . 3 mM PMSF.
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Mono 0 Anion Exchange Chromatography :
The thrombin-cleaved p3 8 kinase was further purified
by FPLC-anion exchange chromatography. Thrombin-cleaved
sample was diluted 2 -fold with Buffer A (25 mM HEPES , pH
5 7.5, 25 mM beta-glycerophosphate, 2 mM DTT, 5% glycerol)
and injected onto a Mono Q HR 10/10 (Pharmacia) anion
exchange column equilibrated with Buffer A. The column
was eluted with a 160 ml 0.1 M-0.6 M NaCl/Buffer A
gradient (2 ml/minute flowrate) . The p38 kinase peak
10 eluting at 200 mM NaCl was collected and concentrated to
3-4 ml with a Filtron 10 concentrator (Filtron Corp.) .
Sephacrvl SI 0 0 Gel Filtration Chromatography:
The concentrated Mono Q- p3 8 kinase purified sample
15 was purified by gel filtration chromatography (Pharmacia
HiPrep 26/60 Sephacryl S100 column equilibrated with
Buffer B (50 mM HEPES, pH 7 . 5 , 50 mM NaCl, 2 mM DTT, 5%
glycerol) ) . Protein was eluted from the column with
Buffer B at a 0.5 ml /minute flowrate and protein was
2 0 detected by absorbance at 280 nm. Fractions containing
p3 8 kinase (detected by SDS-polyacrylamide gel
electrophoresis) were pooled and frozen at -80 °C.
Typical purified protein yields from 5 L E. coli shake
flasks fermentations were 35 mg p38 kinase.
25
In Vitro Assay
The ability of compounds to inhibit human p3 8 kinase
alpha was evaluated using two in vitro assay methods . In
the first method, activated human p3 8 kinase alpha
3 0 phosphorylates a biotinylated substrate, PHAS-I
(phosphorylated heat and acid stable protein-insulin
inducible) , in the presence of gamma 32 P-ATP ( 32 P-ATP) .
PHAS-I was biotinylated prior to the assay and provides a
means of capturing the substrate which is phosphorylated
35 during the assay. p38 Kinase was activated by MKK6 .
Compounds were tested in 10 fold serial dilutions over
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the range of 100 //M to 0.001 fiM using 1% DMSO . Each
concentration of inhibitor was tested in triplicate.
All reactions were carried out in 96 well
polypropylene plates. Each reaction well contained 25 mM
5 HEPES pH 7.5, 10 mM magnesium acetate and 50 /xM unlabeled
ATP. Activation of p38 was required to achieve
sufficient signal in the assay. Biotinylated PHAS-I was
used at 1-2 /xg per 5 0 /xl reaction volume, with a final
concentration of 1.5 /xM . Activated human p3 8 kinase
10 alpha was used at 1 /xg per 50 /xl reaction volume
representing a final concentration of 0.3 /xM. Gamma 32p_
ATP was used to follow the phosphorylation of PHAS-I.
32 P-ATP has a specific activity of 3000 Ci/mmol and was
used at 1.2 /xCi per 50 /xl reaction volume. The reaction
15 proceeded either for one hour or overnight at 3 0 °C.
Following incubation, 2 0 /xl of reaction mixture was
transferred to a high capacity streptavidin coated filter
plate (SAM-streptavidin-matrix, Promega) prewetted with
phosphate buffered saline. The transferred reaction mix
20 was allowed to contact the streptavidin membrane of the
Promega plate for 1-2 minutes. Following capture of
biotinylated PHAS-I with 32p incorporated, each well was
washed to remove unincorporated 32 P-ATP three times with
2M NaCl, three washes of 2M NaCl with 1% phosphoric,
25 three washes of distilled water and finally a single wash
of 95% ethanol . Filter plates were air dried and 20 /xl
of scintillant was added. The plates were sealed and
counted .
A second assay format was also employed that is
3 0 based on p3 8 kinase alpha induced phosphorylation of
EGFRP (epidermal growth factor receptor peptide, a 21
mer) in the presence of 33 P-ATP. Compounds were tested in
10 fold serial dilutions over the range of 100/xM to
0.001/xM in 1% DMSO. Each concentration of inhibitor was
35 tested in triplicate. Compounds were evaluated in 50/xl
reaction volumes in the presence of 25 mM Hepes pH 7.5,
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10 mM magnesium acetate, 4% glycerol, 0.4% bovine serum
albumin, 0 . 4mM DTT, 5 0/xM unlabeled ATP, 2 5 fig EGFRP
(200/xM) , and 0.05 uCi gamma 33 P-ATP. Reactions were
initiated by addition of 0.09 fig of activated, purified
5 human GST-p3 8 kinase alpha. Activation was carried out
using GST-MKK6 (5:1, p3 8 : MKK6 ) for one hour at 30 °C in
the presence of 50/zM ATP. Following incubation for 60
minutes at room temperature, the reaction was stopped by
addition of 150/il of AG 1X8 resin in 900 mM sodium
10 formate buffer, pH 3.0 (1 volume resin to 2 volumes
buffer) . The mixture was mixed three times with
pipetting and the resin was allowed to settle. A total
of 50/il of clarified solution head volume was transferred
from the reaction wells to Microlite-2 plates. 150/^1 of
15 Microscint 40 was then added to each well of the
Microlite plate, and the plate was sealed, mixed, and
counted .
TNF Cell Assays
20
Method of Isolation of Human Peripheral Blood Mononuclear
Cells :
Human whole blood was collected in Vacutainer tubes
containing EDTA as an anticoagulant. A blood sample (7
25 ml) was carefully layered over 5 ml PMN Cell Isolation
Medium (Robbins Scientific) in a 15 ml round bottom
centrifuge tube. The sample was centrifuged at 450-500 x
g for 30-35 minutes in a swing out rotor at room
temperature. After centrif ugat ion, the top band of cells
30 were removed and washed 3 times with PBS w/o calcium or
magnesium. The cells were centrifuged at 400 x g for 10
minutes at room temperature. The cells were resuspended
in Macrophage Serum Free Medium (Gibco BRL) at a
concentration of 2 million cells/ml.
35
LPS Stimulation of Human PBMs :
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PBM cells (0.1 ml, 2 million/ ml) were co-incubated
with 0 . 1 ml compound (10-0.41 pM, final concentration)
for 1 hour in flat bottom 96 well microtiter plates.
Compounds were dissolved in DMSO initially and diluted in
5 TCM for a final concentration of 0.1% DMSO. LPS
(Calbiochem, 2 0 ng/ml , final concentration) was then
added at a volume of 0.010 ml. Cultures were incubated
overnight at 3 7 °C. Supernatant s were then removed and
tested by ELISA for TNF-a and ILl-b. Viability was
10 analyzed using MTS . After 0.1 ml supernatant was
collected, 0.020 ml MTS was added to remaining 0.1 ml
cells. The cells were incubated at 37 °C for 2-4 hours,
then the O.D. was measured at 490-650 nM.
15 Maintenance and Differentiation of the U93 7 Human
Histiocytic Lymphoma Cell Line:
U937 cells (ATCC) were propagated in RPMI 1640
containing 10% fetal bovine serum, 100 IU/ml penicillin,
100 /xg/ml streptomycin, and 2 mM glut amine (Gibco) .
20 Fifty million cells in 100 ml media were induced to
terminal monocytic differentiation by 24 hour incubation
with 20 ng/ml phorbol 12-myristate 13-acetate (Sigma) .
The cells were washed by centrif ugation (200 x g for 5
min) and resuspended in 100 ml fresh medium. After 24-48
25 hours, the cells were harvested, centrif uged, and
resuspended in culture medium at 2 million cells/ml.
LPS Stimulation of TNF production by U937 Cells:
U937 cells (0.1 ml, 2 million/ml) were incubated
3 0 with 0 . 1 ml compound (0.004-50 /jlM, final concentration)
for 1 hour in 96 well microtiter plates. Compounds were
prepared as 10 mM stock solutions in DMSO and diluted in
culture medium to yield a final DMSO concentration of
0.1% in the cell assay. LPS (E coli, 100 ng/ml final
35 concentration) was then added at a volume of 0.02 ml.
After 4 hour incubation at 3 7°C, the amount of TNF-a;
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released in the culture medium was quantitated by ELISA.
Inhibitory potency is expressed as IC50 (/uM) .
Rat Assay
5 The efficacy of the novel compounds in blocking the
production of TNF also was evaluated using a model based
on rats challenged with LPS. Male Harlen Lewis rats
[Sprague Dawley Co.] were used in this model. Each rat
weighed approximately 3 00 g and was fasted overnight
10 prior to testing. Compound administration was typically
by oral gavage (although intraperitoneal, subcutaneous
and intravenous administration were also used in a few
instances) 1 to 24 hours prior to the LPS challenge.
Rats were administered 30 ^ig/kg LPS [salmonella typhosa,
15 Sigma Co.] intravenously via the tail vein. Blood was
collected via heart puncture 1 hour after the LPS
challenge. Serum samples were stored at -20 °C until
quantitative analysis of TNF-a by Enzyme Linked- Immuno-
sorbent Assay ("ELISA") [Biosource] . Additional details
20 of the assay are set forth in Perretti, M. , et al . , Br .
J . Pharmacol . (1993), 110, 868-874, which is incorporated
by reference in this application.
Mouse Assay
25
Mouse Model Of LPS-Induced TNF Alpha Production:
TNF alpha was induced in 10-12 week old BALB/c
female mice by tail vein injection with 100 ng
lipopolysaccharide (from S. Typhosa) in 0.2 ml saline.
3 0 One hour later mice were bled from the retroorbital sinus
and TNF concentrations in serum from clotted blood were
quantified by ELISA. Typically, peak levels of serum TNF
ranged from 2-6 ng/ml one hour after LPS injection.
The compounds tested were administered to fasted
3 5 mice by oral gavage as a suspension in 0.2 ml of 0.5%
methylcellulose and 0.025% Tween 20 in water at 1 hour or
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6 hours prior to LPS injection. The 1 hour protocol
allowed evaluation of compound potency at Cmax plasma
levels whereas the 6 hour protocol allowed estimation of
compound duration of action. Efficacy was determined at
5 each time point as percent inhibition of serum TNF levels
relative to LPS injected mice that received vehicle only.
Induction And Assessment Of Collagen- Induced Arthritis In
Mice :
10 Arthritis was induced in mice according to the
procedure set forth in J.M. Stuart, Collagen Autoimmune
Arthritis, Annual Rev. Immunol. 2:199 (1984), which is
incorporated herein by reference. Specifically,
arthritis was induced in 8-12 week old DBA/1 male mice by
15 injection of 50 /zg of chick type II collagen (CII)
(provided by Dr. Marie Griffiths, Univ. of Utah, Salt
Lake City, UT) in complete Freund' s adjuvant (Sigma) on
day 0 at the base of the tail. Injection volume was 100
/il . Animals were boosted on day 21 with 50 /xg of CII in
20 incomplete Freund' s adjuvant (100 volume) . Animals
were evaluated several times each week for signs of
arthritis. Any animal with paw redness or swelling was
counted as arthritic. Scoring of arthritic paws was
conducted in accordance with the procedure set forth in
25 Wooley et al . , Genetic Control of Type II Collagen
Induced Arthritis in Mice: Factors Influencing Disease
Suspectibility and Evidence for Multiple MHC Associated
Gene Control., Trans . Proc . , 15:180 (1983). Scoring of
severity was carried out using a score of 1-3 for each
30 paw (maximal score of 12/mouse) . Animals displaying any
redness or swelling of digits or the paw were scored as
1. Gross swelling of the whole paw or deformity was
scored as 2. Ankylosis of joints was scored as 3.
Animals were evaluated for 8 weeks. 8-10 animals per
3 5 group were used.
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Preparation And Administration Of Compounds:
The compounds tested on mice having collagen- induced
arthritis were prepared as a suspension in 0.5%
methylcelluose (Sigma, St. Louis, MO), 0.025% Tween 20
5 (Sigma) . The compound suspensions were administered by
oral gavage in a volume of 0.1 ml b.i.d. Administration
began on day 20 post collagen injection and continued
daily until final evaluation on day 56 . Scoring of
arthritic paws was conducted as set forth above.
10 Results obtained using the above-described assays
are set forth in Table I below. p38 assay and U937 cell
assay results are expressed as IC 50 (/xm) . Mouse-LPS assay
results are expressed as percent inhibition.
TABLE I
15
Example
P38Q! 1
p3 8o! 2
U937
mLPS
(6h @
(uM)
(ttM)
(/*M)
(3 0m.pk)
1
30 . 00
13
.35
10
. 00
20
2
6 .
21
10 .
61
3
2 .
55
>10 .
00
4
0 .
23
4 .
70
54
5
1 . 98
5 .
53
6
10 .
00
25
7
5 .
48
10 .
00
8
10 .
00
9
2 .44
3 .
46
0 .
6474
42
10
7 .23
0 .
4
1 .
5987
76
11
0 . 695
10
40
30
12
0 . 941
10
-5
13
0 . 86
>10
22
15
5 . 9
0 .
75
32
1 p38a in vitro results based on PHAS-I assay procedure
3 5 2 p3 8a in vitro results based on EGFRP assay procedure
Also embraced within this invention is a class of
pharmaceutical compositions comprising the active
compounds of this invention in association with one or
40 more non-toxic, pharmaceutically-acceptable carriers
and/or diluents and/or adjuvants (collectively referred
to herein as "carrier" materials) and, if desired, other
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active ingredients. The active compounds of the present
invention may be administered by any suitable route,
preferably in the form of a pharmaceutical composition
adapted to such a route, and in a dose effective for the
5 treatment intended. The active compounds and composition
may, for example, be administered orally, intravascularly
(IV), intraperitoneally , subcutaneously , intramuscularly
(IM) or topically.
For oral administration, the pharmaceutical
10 composition may be in the form of, for example, a tablet,
hard or soft capsule, lozenges, dispensable powders,
suspension or liquid. The pharmaceutical composition is
preferably made in the form of a dosage unit containing a
particular amount of the active ingredient . Examples of
15 such dosage units are tablets or capsules. The active
ingredient may also be administered by injection (IV, IM,
subcutaneous or jet) as a composition wherein, for
example, saline, dextrose, or water may be used as a
suitable carrier. The pH of the composition may be
20 adjusted, if necessary, with suitable acid, base, or
buffer. Suitable bulking, dispersing, wetting or
suspending agents, including mannitol and PEG 4 00, may
also be included in the composition. A suitable
parenteral composition can also include a compound
25 formulated as a sterile solid substance, including
lyophilized powder, in injection vials. Aqueous solution
can be added to dissolve the compound prior to injection.
The amount of therapeutically active compounds that are
administered and the dosage regimen for treating a
3 0 disease condition with the compounds and/or compositions
of this invention depends on a variety of factors,
including the age, weight, sex and medical condition of
the subject, the severity of the inflammation or
inflammation related disorder, the route and frequency of
35 administration, and the particular compound employed, and
thus may vary widely. The pharmaceutical compositions
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may contain active ingredients in the range of about 0 . 1
to 1000 mg, preferably in the range of about 7.0 to 350
mg. A daily dose of about 0.01 to 100 mg/kg body weight,
preferably between about 0.1 and about 50 mg/kg body
5 weight and most preferably between about 0.5 to 3 0 mg/kg
body weight, may be appropriate. The daily dose can be
administered in one to four doses per day. In the case
of skin conditions, it may be preferable to apply a
topical preparation of compounds of this invention to the
10 affected area two to four times a day. For disorders of
the eye or other external tissues, e.g., mouth and skin,
the formulations are preferably applied as a topical gel,
spray, ointment or cream, or as a suppository, containing
the active ingredients in a total amount of, for example,
15 0.075 to 30% w/w, preferably 0.2 to 20% w/w and most
preferably 0.4 to 15% w/w. When formulated in an
ointment, the active ingredients may be employed with
either paraffinic or a water-miscible ointment base.
Alternatively, the active ingredients may be formulated
20 in a cream with an oil-in-water cream base. If desired,
the aqueous phase of the cream base may include, for
example at least 30% w/w of a polyhydric alcohol such as
propylene glycol, butane-1 , 3 -diol , mannitol, sorbitol,
glycerol, polyethylene glycol and mixtures thereof. The
25 topical formulation may desirably include a compound
which enhances absorption or penetration of the active
ingredient through the skin or other affected areas.
Examples of such dermal penetration enhancers include
dimethylsulf oxide and related analogs. The compounds of
3 0 this invention can also be administered by a transdermal
device. Preferably topical administration will be
accomplished using a patch either of the reservoir and
porous membrane type or of a solid matrix variety. In
either case, the active agent is delivered continuously
3 5 from the reservoir or microcapsules through a membrane
into the active agent permeable adhesive, which is in
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contact with the skin or mucosa of the recipient. If the
active agent is absorbed through the skin, a controlled
and predetermined flow of the active agent is
administered to the recipient . In the case of
5 microcapsules, the encapsulating agent may also function
as the membrane. The transdermal patch may include the
compound in a suitable solvent system with an adhesive
system, such as an acrylic emulsion, and a polyester
patch. The oily phase of the emulsions of this invention
10 may be constituted from known ingredients in a known
manner. While the phase may comprise merely an
emulsifier, it may comprise a mixture of at least one
emulsifier with a fat or an oil or with both a fat and an
oil. Preferably, a hydrophilic emulsifier is included
15 together with a lipophilic emulsifier which acts as a
stabilizer. It is also preferred to include both an oil
and a fat. Together, the emulsifier (s) with or without
stabilizer (s) make-up the so-called emulsifying wax, and
the wax together with the oil and fat make up the so-
2 0 called emulsifying ointment base which forms the oily
dispersed phase of the cream formulations. Emulsifiers
and emulsion stabilizers suitable for use in the
formulation of the present invention include Tween 60,
Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl
25 monostearate , and sodium lauryl sulfate, among others.
The choice of suitable oils or fats for the formulation
is based on achieving the desired cosmetic properties,
since the solubility of the active compound in most oils
likely to be used in pharmaceutical emulsion formulations
3 0 is very low. Thus, the cream should preferably be a non-
greasy, non-staining and washable product with suitable
consistency to avoid leakage from tubes or other
containers. Straight or branched chain, mono- or dibasic
alkyl esters such as di-isoadipate, isocetyl stearate,
3 5 propylene glycol diester of coconut fatty acids,
isopropyl myristate, decyl oleate, isopropyl palmitate,
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butyl stearate, 2-ethylhexyl palmitate or a blend of
branched chain esters may be used. These may be used
alone or in combination depending on the properties
required. Alternatively, high melting point lipids such
5 as white soft paraffin and/or liquid paraffin or other
mineral oils can be used.
Formulations suitable for topical administration to
the eye also include eye drops wherein the active
ingredients are dissolved or suspended in suitable
10 carrier, especially an aqueous solvent for the active
ingredients. The antiinflammatory active ingredients are
preferably present in such formulations in a
concentration of 0.5 to 20%, advantageously 0.5 to 10%
and particularly about 1.5% w/w. For therapeutic
15 purposes, the active compounds of this combination
invention are ordinarily combined with one or more
adjuvants appropriate to the indicated route of
administration. If administered per os, the compounds
may be admixed with lactose, sucrose, starch powder,
20 cellulose esters of alkanoic acids, cellulose alkyl
esters, talc, stearic acid, magnesium stearate, magnesium
oxide, sodium and calcium salts of phosphoric and
sulfuric acids, gelatin, acacia gum, sodium alginate,
polyvinylpyrrolidone, and/or polyvinyl alcohol, and then
25 tableted or encapsulated for convenient administration.
Such capsules or tablets may contain a controlled-release
formulation as may be provided in a dispersion of active
compound in hydroxypropylmethyl cellulose. Formulations
for parenteral administration may be in the form of
30 aqueous or non-aqueous isotonic sterile injection
solutions or suspensions. These solutions and
suspensions may be prepared from sterile powders or
granules having one or more of the carriers or diluents
mentioned for use in the formulations for oral
35 administration. The compounds may be dissolved in water,
polyethylene glycol, propylene glycol, ethanol , corn oil,
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cottonseed oil, peanut oil, sesame oil, benzyl alcohol,
sodium chloride, and/or various buffers. Other adjuvants
and modes of administration are well and widely known in
the pharmaceutical art.
5 All patent documents listed herein are incorporated
by reference. Although this invention has been described
with respect to specific embodiments, the details of
these embodiments are not to be construed as limitations.
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WHAT IS CLAIMED IS:
1 . A compound of Formula I
5 wherein
R 1 is selected from hydrido, alkyl, cycloalkyl,
alkenyl, alkynyl, heterocyclyl , cycloalkylalkylene ,
haloalkyl, hydroxyalkyl , aralkyl, alkoxyalkyl,
mercaptoalkyl , alkyl thioalkylene , amino, alkylamino,
10 arylamino, aminoalkyl, alkylaminoalkylene ,
heterocyclylalkylene , aminocarbonylalkylene , and
alkylaminocarbonylalkylene ; and
R 2 is selected from hydrido, alkyl, alkenyl, alkynyl,
heterocyclyl, haloalkyl, heterocyclylalkyl , amino,
15 alkylamino, aminoalkyl, alkoxy, alkylthio, carboxy,
alkoxycarbonyl , carboxyalkyl , aminocarbonylamino ,
alkylaminocarbonylamino, alkylsulf onyl , aminosulf onyl ,
al kyl sul f onyl amino , aminosul f onyl amino ,
alkylaminosulf onylamino, and alkynylamino ; wherein the
2 0 heterocyclyl and heterocyclylalkyl groups are optionally
substituted with one or more radicals independently
selected from alkylthio, alkylsulf onyl , alkylsulf inyl ,
halo, alkyl, alkoxy, aryloxy, aralkoxy, heterocyclyl,
haloalkyl, amino, cyano, and hydroxy; and
2 5 Ar 1 is aryl optionally substituted with one or more
radicals independently selected from halo, alkyl,
alkenyl, alkynyl, alkoxy, alkenoxy, alkyldioxy,
alkylthio, alkylsulf inyl , alkylsul f onyl , amino,
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aminocarbonyl , cyano, alkoxycarbonyl , formyl,
aminosulf onyl , alkylamino, nitro, arylamino,
alkylcarbonylamino , halosulf onyl , aminoalkyl, and
haloalkyl ; and
5 HetAr 2 is pyridinyl, pyrimidinyl or quinolinyl
optionally substituted with one or more radicals
independently selected from alkylthio, alkylsulf onyl ,
alkylsulf inyl , halo, alkyl, heterocyclyl , alkoxy,
aralkoxy, haloalkyl, amino, cyano, aralkyl , alkylamino,
10 cycloalkylamino, cycloalkenylamino, arylamino,
alkynylamino , and aralkylamino ; or
a pharmaceut ically-acceptable salt or a tautomer
thereof .
2 . A compound of Claim 1 wherein
R 1 is selected from hydrido, lower alkyl, lower
cycloalkyl , lower cycloalkylalkylene , lower haloalkyl,
lower hydroxyalkyl , lower alkenyl , lower alkynyl, lower
5 heterocyclyl, lower aralkyl, lower alkoxyalkyl, lower
mercaptoalkyl , lower alkyl thioalkyl ene , amino, lower
alkylamino, lower arylamino, lower aminoalkyl, lower
alkylaminoalkylene , lower heterocyclylalkylene , lower
aminocarbonylalkylene , and lower
10 alkylaminocarbonylalkylene ; and
R 2 is selected from hydrido, lower alkyl, lower
alkenyl, lower alkynyl, lower haloalkyl, lower
heterocyclyl, lower heterocyclylalkylene, amino, lower
alkylamino, lower alkynylamino, lower aminoalkyl, lower
15 alkylthio, lower carboxy, lower alkoxycarbonyl, lower
carboxyalkyl , lower aminocarbonyl amino, lower
alkylaminocarbonylamino, lower alkylsulf onyl , lower
aminosulf onyl , lower alkylsulf onyl amino, lower
aminosulf onylamino , and lower alkylaminosulf onylamino ,
20 wherein the heterocyclyl and heterocyclylalkyl groups are
optionally substituted with one or more radicals
independently selected from lower alkylthio, lower
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alkylsulf onyl , lower alkylsulf inyl , halo, lower alkyl ,
lower alkoxy, aryloxy, lower heterocyclyl , lower
haloalkyl, amino, and cyano; and
Ar 1 is selected from phenyl, biphenyl, and naphthyl ,
5 wherein Ar 1 is optionally substituted with one or more
radicals independently selected from lower alkyl thio,
lower alkylsulf onyl , aminosul f onyl , halo, lower alkyl,
lower alkenyl, lower alkynyl, lower alkylsulf inyl , cyano,
lower alkoxycarbonyl , aminocarbonyl , f ormyl , lower
10 alkyl carbonyl amino, lower haloalkyl, lower alkoxy, lower
alkenyloxy, lower alkyldioxy, amino, lower alkylamino,
lower aminoalkyl, arylamino, nitro, and halosulf onyl ; and
HetAr 2 is pyridinyl or pyrimidinyl optionally
substituted with one or more radicals independently
15 selected from lower alkylthio, lower alkylsulf onyl , lower
alkylsulf inyl , halo, lower alkyl, lower heterocyclyl,
lower alkoxy, lower aralkoxy, lower haloalkyl, amino,
cyano, lower aralkyl, lower alkylamino, lower
cycloalkylamino , lower arylamino, lower alkynylamino , and
2 0 lower aral kyl amino ; or
a pharmaceutically-acceptable salt or tautomer
thereof .
3 . A Compound of Claim 2 wherein
R 1 is selected from hydrido, methyl, ethyl,
isopropyl, tert -butyl, isobutyl, trichloroethyl ,
pentaf luoroethyl , heptaf luoropropyl , dif luoroethyl ,
5 dif luoropropyl , dichloroethyl , dichloropropyl , vinyl,
allyl, ethynyl , propargyl , morpholinyl, piperidinyl,
piperazinyl, benzyl, phenylethyl, morpholinomethyl ,
morpholinoethyl , pyrrol idinylmethyl , piperazinylmethyl ,
piperidinylmethyl , pyridinylmethyl , thienylmethyl ,
10 methoxymethyl , ethoxymethyl , amino, methylamino,
dimethylamino, phenylamino, methylaminomethyl ,
dimethylaminomethyl , methylaminoethyl ,
dimethylaminoethyl , cyclopropyl, cyclopentyl, cyclohexyl,
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cyclohexylmethyl , hydroxymethyl , hydroxyethyl ,
methylthio, and methylthiomethyl ; and
R 2 is selected from hydrido, methyl, ethyl, propyl,
isopropyl, tert-butyl, isobutyl, f luoromethyl ,
5 dif luoromethyl , trif luoromethyl , chloromethyl ,
dichloromethyl , trichloromethyl , pentaf luoroethyl ,
heptaf luoropropyl , dif luorochloromethyl ,
dichlorof luoromethyl , dif luoroethyl , dif luoropropyl ,
dichloroethyl , dichloropropyl , amino, N-methylamino , N,N-
10 dimethylamino, ethynylamino , propargylamino , piperidinyl ,
piperazinyl, morpholinomethyl , pyrrol idinylmethyl ,
piperazinylmethyl , piperidinylmethyl , pyridinylmethyl ,
thienylmethyl , thiazolylmethyl , oxazolylmethyl ,
pyrimidinylmethyl , quinolylmethyl , isoquinolinylmethyl ,
15 imidazolylmethyl , benzimidazolylmethyl , f urylmethyl ,
pyrazinylmethyl , aminocarbonylamino ,
methylaminocarbonylamino , dimethylaminocarbonylamino ,
ethylaminocarbonyl amino , diethylaminocarbonylamino ,
methyl sulf onylamino , ethyl sulf onyl amino,
2 0 aminosulf onylamino , methylaminosulf onylamino,
dimethylaminosulf onylamino , ethylaminosul f onylamino , and
diethylaminosulf onylamino ; and
Ar 1 is selected from phenyl, biphenyl , and naphthyl ,
wherein Ar 1 is optionally substituted with one or more
2 5 radicals independently selected from methylthio,
methylsulf inyl , methyl sul f onyl , fluoro, chloro, bromo,
aminosulf onyl , methyl, ethyl, isopropyl, tert-butyl,
isobutyl, cyano, methoxycarbonyl , e thoxy car bony 1 ,
aminocarbonyl , methylcarbonylamino , trif luoromethyl ,
3 0 dif luoromethyl , f luoromethyl , trichloromethyl,
dichloromethyl, chloromethyl, allyl, vinyl, ethynyl ,
propargyl , methoxy, ethoxy, propyloxy, n-butoxy, amino,
methylamino, ethylamino, dimethylamino, diethylamino ,
aminomethyl , aminoethyl, N-methyl, N-phenylamino ,
3 5 phenylamino, diphenylamino , nitro, and chlorosulf onyl ;
and
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HetAr 2 is selected from pyridinyl and pyrimidinyl ,
wherein HetAr 2 is optionally substituted with one or more
radicals independently selected from methyl thio,
methylsulf inyl , methylsulf onyl , fluoro, chloro, bromo,
5 methyl, ethyl, isopropyl, tert- butyl, isobutyl, methoxyl ,
ethoxyl , phenoxyl , benzoxyl, phenethyl, trif luoromethyl ,
f luoromethyl , dif luoromethyl , amino, benzylamino,
propargylamino, cyclopropylamino , cyclobutylamino ,
cyclopentylamino , and cyano; or
10 a pharmaceutically-acceptable salt or tautomer
thereof .
4 . A compound of Claim 3 wherein
R 1 is hydrido, methyl, ethyl, hydroxyethyl ,
propargyl , dimethylaminoethyl or morpholinoethyl ; and
R 2 is selected from hydrido, methyl, ethyl, amino,
5 aminocarbonylamino, methylaminocarbonyl amino,
methylsulf onylamino, aminosulf onylamino , and
methylaminosulf onylamino ; and
Ar 1 is phenyl optionally substituted with one or more
radicals independently selected from methylthio,
10 methylsulf inyl , methylsulf onyl , fluoro, chloro, bromo,
aminosulf onyl , methyl, ethyl, isopropyl, tert-butyl,
isobutyl, cyano, methoxycarbonyl , ethoxycarbonyl ,
aminocarbonyl , me thylcarbonyl amino, trif luoromethyl ,
dif luoromethyl , f luoromethyl , trichloromethyl ,
15 dichloromethyl , chloromethyl , methoxy, ethoxy, propyloxy,
n-butoxy, amino, methylamino, ethylamino, dimethylamino ,
diethylamino, aminomethyl , aminoethyl , N-methyl, N-
phenylamino, phenylamino, diphenyl amino , nitro, and
chlorosulf onyl ; and
20 HetAr 2 is optionally substituted with one or more
radicals independently selected from methylthio,
methylsulf inyl , methylsulf onyl , fluoro, chloro, bromo,
methyl, ethyl, isopropyl, tert-butyl, isobutyl, methoxyl,
ethoxyl, phenoxyl, benzoxyl, trif luoromethyl ,
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f luoromethyl , dif luoromethyl , amino, propargylamino , and
cyano; or
a pharmaceutically-acceptable salt or a tautomer
thereof .
5 . A compound of Claim 4 wherein
R 1 is hydrido or methyl; and
R 2 is hydrido or methyl; and
Ar 1 is phenyl which is optionally substituted with
5 one or more radicals independently selected fluoro,
chloro, methyl, ethyl, trif luoromethyl , methoxy, ethoxy,
dimethylamino , and nitro; and
HetAr 2 is optionally substituted with one or more
radicals independently selected from methyl, chloro,
10 fluoro, and trif luoromethyl ; or
a pharmaceutically-acceptable salt or tautomer
thereof .
6. A compound of Claim 1 wherein R 2 is hydrido.
7. A compound of Claim 2 wherein R 2 is hydrido.
8. A compound of Claim 3 wherein R 2 is hydrido.
9. A compound of Claim 4 wherein R 2 is hydrido.
10. A compound of Claim 5 wherein R 2 is hydrido.
11. A compound of Claim 1 wherein HetAr 2 is
optionally substituted pyridinyl .
12. A compound of Claim 2 wherein HetAr 2 is
optionally substituted pyridinyl.
13 . A compound of Claim 3 wherein HetAr 2 is
optionally substituted pyridinyl.
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71
14 . A compound of Claim 4 wherein HetAr 2 is
optionally substituted pyridinyl .
15 . A compound of Claim 5 wherein HetAr 2 is
optionally substituted pyridinyl.
16. A compound of Claim 1 wherein R 2 is hydrido, Ar 1
is optionally substituted phenyl, and HetAr 2 is optionally
substituted pyridinyl .
17. A compound of Claim 2 wherein R 2 is hydrido, Ar 1
is optionally substituted phenyl, and HetAr 2 is optionally
substituted pyridinyl .
18. A compound of Claim 3 wherein R 2 is hydrido, Ar 1
is optionally substituted phenyl, and HetAr 2 is optionally
substituted pyridinyl.
19 . A compound of Claim 4 wherein R 2 is hydrido and
HetAr 2 is optionally substituted pyridinyl .
20. A compound of Claim 5 wherein R 2 is hydrido and
HetAr 2 is optionally substituted pyridinyl .
21. A compound of Claim 4 selected from the
compounds, their tautomers and their pharmaceut ically
acceptable salts, of the group consisting of
4 - (3 -methyl -4 -phenyl - lH-pyrazol - 5 -yl ) pyridine ;
4- (4-f luorophenyl) -5- (4 -pyridinyl ) - lH-pyrazol - 3 -amine ;
N- [4 (4-f luorophenyl) -5- (4 -pyridinyl ) - lH-pyrazol - 3 -
yl ] methanesul f onamide ;
N- [4- (4 - f luorophenyl ) -5- (4 -pyridinyl ) - lH-pyrazol-3 -yl] -
N' -methyl sulf amide ;
[4- (4-f luorophenyl) -5- (4 -pyridinyl ) -lH-pyrazol-3-yl] urea;
[4- (4-f luorophenyl) -5- (4 -pyridinyl ) - lH-pyrazol - 3 -
yl] sulf amide;
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4- (4 -chlorophenyl) - 1 -methyl -3 - (4-pyridinyl) -lH-pyrazol-5-
amine ;
N- [4- (4 - f luorophenyl ) -5- (4-pyridinyl) - lH-pyrazol -3 -yl] -
N' -methylurea;
5 4- [4- (4 - f luorophenyl ) - lH-pyrazol -3 -yl] pyridine ;
4- [4- (4 -f luorophenyl) - 1 -methyl -lH-pyrazol- 3 -yl] pyridine;
4 - (4 - f luorophenyl) -3 - (4-pyridinyl) - lH-pyrazole- 1 -ethanol ;
4- (4 -f luorophenyl) -N, N-dimethyl - 3 - (4-pyridinyl) -1H-
pyrazole - 1 -ethanamine ;
10 4- [2- [4- (4 -f luorophenyl) -3- (4-pyridinyl) -lH-pyrazol-1-
yl ] ethyl ] morphol ine ;
4 - [4 - (4 -chlorophenyl ) - lH-pyrazol -3 -yl] pyridine ;
1 -methyl -4- [2- [4- (4 - f luorophenyl ) -3- (4-pyridinyl) -1H-
pyrazol - 1 -yl ] ] piperidine ; and
15 1 -methyl -4- [2- [4- (4 - f luorophenyl ) -5- (4-pyridinyl) -1H-
pyrazol - 1 -yl ] piperidine .
22 . A compound of Formula I
wherein
R 1 is selected from hydrido, lower alkyl, lower
5 cycloalkyl, lower cycloalkylalkylene , lower haloalkyl,
lower hydroxyalkyl , lower alkynyl , lower aralkyl , lower
alkoxyalkyl, lower mercaptoalkyl , lower
alkyl thioalkylene , amino, lower alkylamino, lower
arylamino, lower aminoalkyl, lower alkylaminoalkylene ,
10 lower heterocyclylalkylene , lower aminocarbonyl alkyl ene ,
and lower alkylaminocarbonylalkylene ; and
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R 2 is selected from hydrido, lower alkyl , lower
cycloalkyl, lower cycloalkenyl , aryl selected from phenyl
and biphenyl , lower aralkyl , lower haloalkyl, lower
heterocyclyl , lower het erocyc lyl alkylene , amino, lower
5 arylamino, lower alkylamino, lower alkynylamino , lower
aminocarbonyl amino , lower alkylaminocarbonylamino ,
sulfonyl, lower alkylsulf onylamino , lower
aminosulf onylamino , and lower alkyl aminosulf onylamino,
wherein the cycloalkyl, aryl and heterocyclyl groups are
10 optionally substituted with one or more radicals
independently selected from lower alkylthio, lower
alkylsulf onyl , lower alkylsulf inyl , halo, lower alkyl,
lower alkoxy, aryloxy, lower heterocyclyl, lower
haloalkyl, amino, and cyano; and
15 Ar 1 is phenyl optionally substituted with one or more
radicals independently selected from halo, lower alkyl,
lower alkenyl, lower alkynyl, lower alkoxy, lower
alkylthio, lower alkylsulf inyl , lower alkylsulf onyl ,
amino, aminocarbonyl, cyano, lower alkoxycarbonyl ,
20 formyl, aminosulf onyl , lower alkylamino, nitro, lower
arylamino, loewr alkylcarbonylamino , halosulf onyl , lower
aminoalkyl , and lower haloalkyl; and
HetAr 2 is pyridinyl optionally substituted with one
or more radicals independently selected from lower
25 alkylthio, lower alkylsulf onyl , lower alkylsulf inyl ,
halo, lower alkyl, lower heterocyclyl, lower alkoxy,
lower aralkoxy, lower haloalkyl, amino, cyano, lower
aralkyl, lower alkylamino, lower cycloalkylamino , lower
aralkylamino, and lower arylamino; or
3 0 a pharmaceut ically-acceptable salt or a tautomer
thereof .
23 . A compound of claim 22 wherein
R 1 is hydrido, methyl, hydroxyethyl ,
dimethylaminoethyl , propargyl , or morphol inoethyl ; and
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R 2 is selected from hydrido, methyl, ethyl, amino,
aminocarbonylamino , methyl aminocarbonyl amino ,
methyl sulf onylamino, aminosulf onylamino , and
methylaminosulf onylamino ;
24. A compound of claim 22 wherein R 2 is hydrido.
25. A compound of claim 22 wherein Ar 1 is phenyl
substituted with one or more halogen radicals.
26. A compound of claim 22 wherein R 2 is hydrido and
Ar 1 is phenyl substituted with one or more halogen
radicals .
27. A pharmaceutical composition comprising a
therapeut ically-ef f ective amount of a compound, said
compound selected from the compounds of Claim 1; or a
pharmaceut ically salt or tautomer thereof.
28. A pharmaceutical composition comprising a
therapeut ically-ef f ective amount of a compound, said
compound selected from the compounds of Claim 2 ; or a
pharmaceut ically salt or tautomer thereof.
29. A pharmaceutical composition comprising a
therapeut ically-ef f ective amount of a compound, said
compound selected from the compounds of Claim 3 ; or a
pharmaceut ically salt or tautomer thereof.
30. A pharmaceutical composition comprising a
therapeutically-eff ective amount of a compound, said
compound selected from the compounds of Claim 4; or a
pharmaceut ically salt or tautomer thereof.
31. A pharmaceutical composition comprising a
therapeutically-eff ective amount of a compound, said
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compound selected from the compounds of Claim 5; or a
pharmaceutically salt or tautomer thereof .
32 . A pharmaceutical composition comprising a
therapeutically-ef f ective amount of a compound, said
compound selected from the compounds of Claim 21; or a
pharmaceutically salt or tautomer thereof .
33 . A method of treating a TNF mediated disorder,
said method comprising treating the subject having or
susceptible to such disorder with a therapeut ically-
effective amount of a compound of Formula I
wherein
R 1 is selected from hydrido, alkyl, cycloalkyl,
alkenyl, alkynyl, heterocyclyl , cycloalkylalkylene ,
haloalkyl, hydroxyalkyl , aralkyl, alkoxyalkyl,
10 mercaptoalkyl , alkylthioalkylene , amino, alkylamino,
arylamino, aminoalkyl, alkylaminoalkylene ,
heterocyclylalkylene , aminocarbonylalkylene , and
alkylaminocarbonylalkylene ; and
R 2 is selected from hydrido, alkyl, alkenyl, alkynyl,
15 heterocyclyl, haloalkyl, heterocyclylalkyl , amino,
alkylamino, aminoalkyl, alkoxy, alkylthio, carboxy,
alkoxycarbonyl , carboxyalkyl , aminocarbonyl amino ,
alkylaminocarbonylanrd.no, alkylsulf onyl , aminosulf onyl ,
alkylsulf onylamino, aminosulf onylamino,
20 alkylaminosulf onylamino , and alkynylamino ; wherein the
N
5
(I)
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heterocyclyl and heterocyclylalkyl groups are optionally
substituted with one or more radicals independently
selected from alkylthio, alkylsulf onyl , alkylsulf inyl ,
halo, alkyl, alkoxy, aryloxy, aralkoxy, heterocyclyl,
5 haloalkyl , amino, cyano, and hydroxy; and
Ar 1 is aryl optionally substituted with one or more
radicals independently selected from halo, alkyl,
alkenyl , alkynyl , alkoxy, alkenoxy, alkyldioxy,
alkylthio, alkylsulf inyl , alkylsulf onyl , amino,
10 aminocarbonyl , cyano, alkoxycarbonyl , formyl,
aminosulf onyl , alkylamino, nitro, arylamino,
alkylcarbonylamino, halosulf onyl , aminoalkyl, and
haloalkyl; and
HetAr 2 is pyridinyl , pyrimidinyl or quinolinyl
15 optionally substituted with one or more radicals
independently selected from alkylthio, alkylsulf onyl ,
alkylsulf inyl , halo, alkyl, heterocyclyl, alkoxy,
aralkoxy, haloalkyl, amino, cyano, aralkyl, alkylamino,
cycloalkylamino, cycloalkenylamino, arylamino,
2 0 alkynylamino, and aralkylamino; or
a pharmaceutically- acceptable salt or a tautomer
thereof .
34. A method of treating a p38 kinase mediated
disorder, said method comprising treating the subject
having or susceptible to such disorder with a
therapeutically-ef f ective amount of a compound of Formula
5 I
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wherein
R 1 is selected from hydrido, alkyl, cycloalkyl,
alkenyl , alkynyl , heterocyclyl , cycloalkylalkylene ,
haloalkyl , hydroxyalkyl , aralkyl , alkoxyalkyl,
5 mercaptoalkyl , alkyl thioalkylene , amino, alkylamino,
arylamino, aminoalkyl, alkylaminoalkylene ,
heterocyclylalkylene , aminocarbonylalkylene , and
alkylaminocarbonylalkylene ; and
R 2 is selected from hydrido, alkyl, alkenyl, alkynyl,
10 heterocyclyl, haloalkyl, heterocyclylalkyl , amino,
alkylamino, aminoalkyl, alkoxy, alkylthio, carboxy,
alkoxycarbonyl , carboxyalkyl , aminocarbonylamino ,
alkylaminocarbonylamino, alkylsulf onyl , aminosulf onyl ,
alkylsulf onylamino , aminosulf onylamino,
15 alkyl aminosulf onylamino, and alkynyl ami no ; wherein the
heterocyclyl and heterocyclylalkyl groups are optionally
substituted with one or more radicals independently
selected from alkylthio, alkylsulf onyl , alkylsulf inyl ,
halo, alkyl, alkoxy, aryloxy, aralkoxy, heterocyclyl,
2 0 haloalkyl, amino, cyano, and hydroxy; and
Ar 1 is aryl optionally substituted with one or more
radicals independently selected from halo, alkyl,
alkenyl, alkynyl, alkoxy, alkenoxy, alkyldioxy,
alkylthio, alkylsulf inyl , alkylsulf onyl , amino,
25 aminocarbonyl , cyano, alkoxycarbonyl, formyl,
aminosulf onyl , alkylamino, nitro, arylamino,
alkylcarbonylamino , halosulf onyl , aminoalkyl, and
haloalkyl ; and
HetAr 2 is pyridinyl, pyrimidinyl or quinolinyl
30 optionally substituted with one or more radicals
independently selected from alkylthio, alkylsulf onyl ,
alkylsulf inyl , halo, alkyl, heterocyclyl, alkoxy,
aralkoxy, haloalkyl, amino, cyano, aralkyl, alkylamino,
cycloalkyl amino, cycloalkenylamino , arylamino,
3 5 alkynylamino , and aralkyl amino; or
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a pharmaceutically-acceptable salt or a tautomer
thereof .
35. A method of treating inflammation, said method
comprising treating the subject having or susceptible to
such condition with a therapeutically- ef f ective amount of
a compound of Formula I
5 r1 (I)
wherein
R 1 is selected from hydrido, alkyl, cycloalkyl,
alkenyl , alkynyl, heterocyclyl , cycloalkylalkylene ,
haloalkyl , hydroxyalkyl , aralkyl , alkoxyalkyl,
10 mercaptoalkyl , alkylthioalkylene , amino, alkylamino,
arylamino, aminoalkyl, alkylaminoalkylene ,
heterocyclylalkylene , aminocarbonylalkylene , and
alkylaminocarbonylalkylene ; and
R 2 is selected from hydrido, alkyl, alkenyl, alkynyl,
15 heterocyclyl, haloalkyl, heterocyclylalkyl , amino,
alkylamino, aminoalkyl, alkoxy, alkyl thio, carboxy,
alkoxycarbonyl , carboxyalkyl , aminocarbonyl amino ,
alkyl aminocarbonylamino , alkylsulf onyl , aminosulf onyl ,
alkyl sulf onyl amino , aminosulf onyl amino,
2 0 alkylaminosulf onylamino , and alkynylamino ; wherein the
heterocyclyl and heterocyclylalkyl groups are optionally
substituted with one or more radicals independently
selected from alkylthio, alkylsulf onyl , alkyl sul finyl ,
halo, alkyl, alkoxy, aryloxy, aralkoxy, heterocyclyl,
2 5 haloalkyl, amino, cyano, and hydroxy; and
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Ar 1 is aryl optionally substituted with one or more
radicals independently selected from halo, alkyl,
alkenyl, alkynyl, alkoxy, alkenoxy, alkyldioxy,
alkylthio, alkylsulf inyl , alkylsulf onyl , amino,
5 aminocarbonyl , cyano, alkoxycarbonyl , f ormyl ,
aminosulf onyl , alkylamino, nitro, arylamino,
alkylcarbonylamino, halosul f onyl , aminoalkyl , and
haloalkyl; and
HetAr 2 is pyridinyl , pyrimidinyl or quinolinyl
10 optionally substituted with one or more radicals
independently selected from alkylthio, alkylsulf onyl ,
alkylsulf inyl , halo, alkyl, heterocyclyl , alkoxy,
aralkoxy, haloalkyl, amino, cyano, aralkyl, alkylamino,
eye lo alkyl amino, cycloalkenylamino, arylamino,
15 alkynylamino , and aralkylamino ; or
a pharmaceutically-acceptable salt or a tautomer
thereof .
36. A method of treating arthritis, said method
comprising treating the subject having or susceptible to
such condition with a therapeutical ly-ef f ective amount of
a compound of Formula I
5 r1 (I)
wherein
R 1 is selected from hydrido, alkyl, cycloalkyl,
alkenyl, alkynyl, heterocyclyl, cycloalkylalkylene ,
haloalkyl, hydroxyalkyl , aralkyl, alkoxyalkyl,
10 mercaptoalkyl , alkyl thioalkyl ene , amino, alkylamino,
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arylamino, aminoalkyl, alkylaminoalkylene ,
heterocyclylalkylene , amino c arbony 1 al ky 1 ene , and
alkylaminocarbonylalkylene ; and
R 2 is selected from hydrido, alkyl , alkenyl , alkynyl ,
5 heterocyclyl , haloalkyl, heterocyclylalkyl , amino,
alkylamino, aminoalkyl, alkoxy, alkyl thio, carboxy,
alkoxycarbonyl , carboxyalkyl , aminocarbonyl amino,
alkylaminocarbonylamino, alkylsulf onyl , aminosulf onyl ,
alkylsulf onyl amino, aminosulf onyl amino,
10 alkyl aminosulf onyl amino , and alkynylamino; wherein the
heterocyclyl and heterocyclylalkyl groups are optionally
substituted with one or more radicals independently
selected from alkylthio, alkylsulf onyl , alkylsulf inyl ,
halo, alkyl, alkoxy, aryloxy, aralkoxy, heterocyclyl,
15 haloalkyl, amino, cyano, and hydroxy; and
Ar 1 is aryl optionally substituted with one or more
radicals independently selected from halo, alkyl,
alkenyl, alkynyl, alkoxy, alkenoxy, alkyldioxy,
alkylthio, alkylsulf inyl , alkylsulf onyl , amino,
2 0 aminocarbonyl, cyano, alkoxycarbonyl, f ormyl ,
aminosulf onyl , alkylamino, nitro, arylamino,
alkyl carbonylamino, halosulf onyl , aminoalkyl, and
haloalkyl; and
HetAr 2 is pyridinyl , pyrimidinyl or quinolinyl
2 5 optionally substituted with one or more radicals
independently selected from alkylthio, alkylsulf onyl ,
alkylsulf inyl , halo, alkyl, heterocyclyl, alkoxy,
aralkoxy, haloalkyl, amino, cyano, aralkyl , alkylamino,
cycloalkylamino, cycloalkenyl amino, arylamino,
3 0 alkynylamino, and aralkylamino ; or
a pharmaceutically-acceptable salt or a tautomer
thereof .
37. The method of Claim 33 wherein the TNF mediated
disorder is selected from the group of disorders
consisting of bone resorption, graft vs. host reaction,
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atherosclerosis, arthritis, osteoarthritis, rheumatoid
arthritis, gout, psoriasis, topical inflammatory disease
state, adult respiratory distress syndrome, asthma,
chronic pulmonary inflammatory disease, cardiac
5 reperfusion injury, renal reperfusion injury, thrombus,
glomerulonephritis, Crohn's disease, ulcerative colitis,
inflammatory bowel disease and cachexia.
38. The method of Claim 33 wherein the TNF mediated
disorder is inflammation.
39. The method of Claim 33 wherein the TNF mediated
disorder is arthritis.
40. The method of Claim 33 wherein the TNF mediated
disorder is asthma.
41. The method of claim 33 wherein the compound is
selected from the compounds, their tautomers and their
pharmaceutically acceptable salts, of the group
consisting of
5 4- ( 3 -methyl -4 -phenyl -lH-pyrazol- 5 -yl) pyridine;
4- (4 -f luorophenyl) -5- (4 -pyridinyl ) - lH-pyrazol -3 -amine ;
N- [4 (4 -f luorophenyl) -5- (4 -pyridinyl ) -lH-pyrazol-3 -
yl] methanesulf onamide ;
N- [4- (4 -f luorophenyl) -5- (4 -pyridinyl ) -lH-pyrazol-3 -yl] -
10 N' -methylsulf amide ;
[4- (4 -f luorophenyl) -5- (4 -pyridinyl ) - lH-pyrazol - 3 -yl ] urea ;
[4- (4 -f luorophenyl ) -5- (4 -pyridinyl ) -lH-pyrazol-3 -
yl] sulf amide;
4- (4 -chlorophenyl) -l-methyl-3- (4 -pyridinyl ) -lH-pyrazol-5-
1 5 amine ;
N- [4- (4 -f luorophenyl) -5- (4 -pyridinyl ) - lH-pyrazol - 3 -yl] -
N' -methylurea ;
4- [4- (4 -f luorophenyl) - lH-pyrazol- 3 -yl] pyridine ;
4- [4- (4 -f luorophenyl) - 1 -methyl - lH-pyrazol - 3 -yl] pyridine ;
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4- (4 -f luorophenyl) -3- (4 -pyridinyl ) - lH-pyrazole- 1-ethanol ;
4- (4 -f luorophenyl) -N,N-dimethyl-3 - (4 -pyridinyl ) -1H-
pyrazole- 1 - ethanamine ;
4- [2- [4- (4 -f luorophenyl) -3- (4 -pyridinyl ) - lH-pyrazol -1 -
5 yl] ethyl] morpholine;
4- [4- (4-chlorophenyl) - lH-pyrazol - 3 -yl ] pyridine ;
1 -methyl -4- [2- [4- (4 - f luorophenyl ) -3- (4 -pyridinyl ) -1H-
pyrazol-l-yl] ] piperidine; and
l-methyl-4- [2- [4- (4 -f luorophenyl) -5- (4 -pyridinyl ) -1H-
10 pyrazol-l-yl] piperidine .
42. The method of Claim 34 wherein the disorder is a
p3 8a kinase mediated disorder.
43. The method of Claim 34 wherein the P38 kinase
mediated disorder is selected from the group of disorders
consisting of bone resorption, graft vs. host reaction,
atherosclerosis, arthritis, osteoarthritis, rheumatoid
5 arthritis, gout, psoriasis, topical inflammatory disease
state, adult respiratory distress syndrome, asthma,
chronic pulmonary inflammatory disease, cardiac
reperfusion injury, renal reperfusion injury, thrombus,
glomerulonephritis, Crohn's disease, ulcerative colitis,
10 inflammatory bowel disease and cachexia.
44. The method of Claim 34 wherein the p38 kinase
mediated disorder is inflammation.
45. The method of Claim 34 wherein the p38 kinase
mediated disorder is arthritis.
46. The method of Claim 34 wherein the p38 kinase
mediated disorder is asthma.
47 . The method of claim 34 wherein the compound is
selected from the compounds, their tautomers and their
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pharmaceutically acceptable salts, of the group
consisting of
4 - ( 3 -methyl -4 -phenyl - lH-pyrazol - 5 -yl ) pyridine ;
4- (4 -f luorophenyl) -5- (4 -pyridinyl) - lH-pyrazol -3 -amine ;
5 N- [4 (4 -f luorophenyl) -5- (4 -pyridinyl ) -lH-pyrazol-3-
yl] methanesulf onamide ;
N- [4- (4 -f luorophenyl) -5- ( 4 -pyridinyl ) - lH-pyrazol -3 -yl] -
N' -methylsulf amide ;
[4- (4 -f luorophenyl) -5- (4 -pyridinyl ) -lH-pyrazol-3-yl] urea;
10 [4- (4 -f luorophenyl) -5- (4 -pyridinyl ) - lH-pyrazol -3 -
yl] sulf amide;
4- (4 -chlorophenyl) -1 -methyl -3- (4 -pyridinyl ) -lH-pyrazol-5-
amine ;
N- [4- (4 - f luorophenyl ) -5- (4 -pyridinyl ) - lH-pyrazol - 3 -yl ] -
15 N' -methylurea;
4- [4- (4 -f luorophenyl) - lH-pyrazol -3 -yl ] pyridine ;
4- [4- (4 -f luorophenyl) - 1 -methyl - lH-pyrazol - 3 -yl ] pyridine ;
4- (4 -f luorophenyl) -3- (4 -pyridinyl ) - lH-pyrazole- 1 -ethanol ;
4- (4 - f luorophenyl) -N,N-dimethyl-3- (4 -pyridinyl ) -1H-
20 pyrazole-l-ethanamine ;
4- [2- [4- (4 -f luorophenyl) -3- ( 4 -pyridinyl ) - lH-pyrazol - 1 -
yl] ethyl] morpholine ;
4- [4- (4 -chlorophenyl) - lH-pyrazol -3 -yl] pyridine ;
l-methyl-4- [2- [4- (4 - f luorophenyl ) -3- (4 -pyridinyl ) -1H-
2 5 pyrazol-l-yl] ] piperidine; and
l-methyl-4- [2- [4- (4 - f luorophenyl ) -5- (4 -pyridinyl ) -1H-
pyrazol - 1 -yl ] piperidine .
48. A compound of claim 1 that is 4-[4-(4-
f luorophenyl )- lH-pyrazol -3 -yl] pyridine or a
pharmaceutically-acceptable salt or a tautomer thereof .
49. The method of claim 33 wherein the compound is
4- [4- (4- f luorophenyl) -lH-pyrazol- 3 -yl] pyridine or a
pharmaceutically-acceptable salt or a tautomer thereof.
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50. The method of claim 34 wherein the compound is
4- [4- (4-f luorophenyl) -lH-pyrazol-3 -yl] pyridine or a
pharmaceutically-acceptable salt or a tautomer thereof.
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